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  • Smart motors and cargo steering drive kinesin-mediated selective transport
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2020-01-20
    Alec T. Nabb; Madeline Frank; Marvin Bentley

    Neurons are polarized cells, with dendrites and axons that require different complements of membrane proteins to fulfill their specialized functions. Membrane proteins are synthesized in the somatodendritic domain and delivered to their target membranes via long-range vesicle transport. Most anterograde vesicle transport is mediated by kinesin motors, but it is unclear how kinesins are targeted to axons or dendrites. Two main models have been proposed to explain kinesin selectivity. In the smart motor model, kinesin selectivity is conferred by a preference of the kinesin motor domain for specific subsets of microtubules. In the cargo steering model, kinesin selectivity is modulated by the vesicular cargo to which the motor is bound. We evaluate the evidence for both models and conclude that while the smart motor model may explain axonal selectivity, cargo steering is required for dendritic selectivity. Future work will determine the relative contributions of these models to polarized transport in living neurons.

    更新日期:2020-01-21
  • Autophagy modulates Aβ accumulation and formation of aggregates in yeast
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2020-01-18
    Prashant R. Bharadwaj; Ralph N. Martins

    Intracellular accumulation of amyloid-β protein (Aβ) is an early event in Alzheimer's disease (AD). The autophagy-lysosomal pathway is an important pathway for maintaining cellular proteostasis and for the removal of damaged organelles and protein aggregates in all eukaryotes. Despite mounting evidence showing that modulating autophagy promotes clearance of Aβ aggregates, the regulatory mechanisms and signalling pathways underlying this process remain poorly understood. In order to gain better insight we used our previously characterised yeast model expressing GFP-Aβ42 to identify genes that regulate the removal of Aβ42 aggregates by autophagy. We report that GFP-Aβ42 is sequestered and is selectively transported to vacuole for degradation and that autophagy is the prominent pathway for clearance of aggregates. Next, to identify genes that selectively promote the removal of Aβ42 aggregates, we screened levels of GFP-Aβ42 and non-aggregating GFP-Aβ42 (19:34) proteins in a panel of 192 autophagy mutants lacking genes involved in regulation and initiation of the pathway, cargo selection and degradation processes. The nutrient and stress signalling genes RRD1, SNF4, GCN4 and SSE1 were identified. Deletion of these genes impaired GFP-Aβ42 clearance and their overexpression reduced GFP-Aβ42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aβ42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.

    更新日期:2020-01-21
  • Identification of MAGUK scaffold proteins as intracellular binding partners of synaptic adhesion protein Slitrk2
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2020-01-08
    Connor Loomis; Aliyah Stephens; Remi Janicot; Usman Baqai; Laura Drebushenko; Jennifer Round

    Synaptic adhesion proteins play a critical role in the formation and maintenance of synapses in the developing nervous system. Errors in synaptic adhesion constitute the molecular basis of many neuropsychiatric disorders, including schizophrenia, bipolar disorder, Tourette syndrome, and autism. Slit- and Trk-like proteins (Slitrks) are a family of leucine-rich repeat containing transmembrane proteins that promote synaptogenesis. These proteins localize to the postsynaptic density, where they induce synapse formation via trans-synaptic interactions with receptor protein tyrosine phosphatases. While trans-synaptic binding partners of Slitrks have been reported, little is known about the intracellular proteins that associate with Slitrks. Here we report an interaction between Slitrk2 and members of the PSD-95 subfamily of membrane associated guanylate kinases (MAGUKs). Coimmunoprecipitation from postnatal mouse brain indicates that PSD-93 and PSD-95 associate with Slitrk2 in vivo. Mapping analysis in yeast demonstrates that Slitrk2 interacts directly with PSD-95 via a non-canonical Src homology 3 (SH3) domain binding motif that associates with the SH3 domain of PSD-95. We also show that PSD-95 induces robust clustering of Slitrk2 in 293T cells, and deletion of the SH3 domain in PSD-95 or the SH3 domain binding motif in Slitrk2 reduces this clustering. These data confirm PSD-95 as the first known intracellular binding partner of Slitrk2. Future studies will examine if Slitrk-MAGUK interactions mediate localization of Slitrks to synaptic sites and facilitate recruitment of additional intracellular signaling molecules involved in postsynaptic differentiation.

    更新日期:2020-01-08
  • Δ9-tetrahydrocannabinol and 2-AG decreases neurite outgrowth and differentially affects ERK1/2 and Akt signaling in hiPSC-derived cortical neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2020-01-07
    Carole Shum; Lucia Dutan; Emily Annuario; Katherine Warre-Cornish; Samuel E. Taylor; Ruth D. Taylor; Laura C. Andreae; Noel J. Buckley; Jack Price; Sagnik Bhattacharyya; Deepak P. Srivastava

    Endocannabinoids regulate different aspects of neurodevelopment. In utero exposure to the exogenous psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), has been linked with abnormal cortical development in animal models. However, much less is known about the actions of endocannabinoids in human neurons. Here we investigated the effect of the endocannabinoid 2-arachidonoyl glycerol (2AG) and Δ9-THC on the development of neuronal morphology and activation of signaling kinases, in cortical neurons derived from human induced pluripotent stem cells (hiPSCs). Our data indicate that the cannabinoid type 1 receptor (CB1R), but not the cannabinoid 2 receptor (CB2R), GPR55 or TRPV1 receptors, is expressed in young, immature hiPSC-derived cortical neurons. Consistent with previous reports, 2AG and Δ9-THC negatively regulated neurite outgrowth. Interestingly, acute exposure to both 2AG and Δ9-THC inhibited phosphorylation of serine/threonine kinase extracellular signal-regulated protein kinases (ERK1/2), whereas Δ9-THC also reduced phosphorylation of Akt (aka PKB). Moreover, the CB1R inverse agonist SR 141716A attenuated the decrease in neurite outgrowth and ERK1/2 phosphorylation induced by 2AG and Δ9-THC. Taken together, our data suggest that hiPSC-derived cortical neurons express CB1Rs and are responsive to exogenous cannabinoids. Thus, hiPSC-neurons may represent a good cellular model for investigating the role of the endocannabinoid system in regulating cellular processes in developing human neurons.

    更新日期:2020-01-07
  • Deficits in developmental neurogenesis and dendritic spine maturation in mice lacking the serine protease inhibitor neuroserpin
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-12-02
    Melanie Hermann, Rebecca Reumann, Katrin Schostak, Dilara Kement, Mathias Gelderblom, Christian Bernreuther, Renato Frischknecht, Angela Schipanski, Sergej Marik, Susanne Krasemann, Diego Sepulveda-Falla, Michaela Schweizer, Tim Magnus, Markus Glatzel, Giovanna Galliciotti
    更新日期:2019-12-02
  • SNAP-25 phosphorylation at Ser187 is not involved in Ca2+ or phorbolester-dependent potentiation of synaptic release
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-30
    Marvin Ruiter, Sébastien Houy, Kasper Engholm-Keller, Mark E. Graham, Jakob B. Sørensen

    SNAP-25, one of the three SNARE-proteins responsible for synaptic release, can be phosphorylated by Protein Kinase C on Ser-187, close to the fusion pore. In neuroendocrine cells, this phosphorylation event potentiates vesicle recruitment into releasable pools, whereas the consequences of phosphorylation for synaptic release remain unclear. We mutated Ser-187 and expressed two mutants (S187C and S187E) in the context of the SNAP-25B-isoform in SNAP-25 knockout glutamatergic autaptic neurons. Whole-cell patch clamp recordings were performed to assess the effect of Ser-187 phosphorylation on synaptic transmission. Blocking phosphorylation by expressing the S187C mutant did not affect synapse density, basic evoked or spontaneous neurotransmission, the readily-releasable pool size or its Ca2+-independent or Ca2+-dependent replenishment. Furthermore, it did not affect the response to phorbol esters, which activate PKC. Expressing S187C in the context of the SNAP-25A isoform also did not affect synaptic transmission. Strikingly, the – potentially phosphomimetic – mutant S187E reduced spontaneous release and release probability, with the largest effect seen in the SNAP-25B isoform, showing that a negative charge in this position is detrimental for neurotransmission, in agreement with electrostatic fusion triggering. During the course of our experiments, we found that higher SNAP-25B expression levels led to decreased paired pulse potentiation, probably due to higher release probabilities. Under these conditions, the potentiation of evoked EPSCs by phorbol esters was followed by a persistent down-regulation, probably due to a ceiling effect. In conclusion, our results indicate that phosphorylation of Ser-187 in SNAP-25 is not involved in modulation of synaptic release by Ca2+ or phorbol esters.

    更新日期:2019-11-30
  • Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease)
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-30
    Carley R. Corado, Jason Pinkstaff, Xuntian Jiang, Evelyn M. Galban, Samantha J. Fisher, Oriane Scholler, Chris Russell, Jessica H. Bagel, Patricia A. ODonnell, Daniel S. Ory, Charles H. Vite, Allison M. Bradbury

    Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe's disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD.

    更新日期:2019-11-30
  • Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-30
    A.A. Wright, M. Todorovic, M. Murtaza, J.A. St John, J.A. Ekberg

    Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.

    更新日期:2019-11-30
  • Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-23
    Jennifer J. O'Brien, James P. O'Callaghan, Diane B. Miller, Suman Chalgeri, Lawrence P. Wennogle, Robert E. Davis, Gretchen L. Snyder, Joseph P. Hendrick

    A novel, potent, and highly specific inhibitor of calcium-calmodulin-dependent phosphodiesterases (PDE) of the PDE1 family, ITI-214, was used to investigate the role of PDE1 in inflammatory responses. ITI-214 dose-dependently suppressed lipopolysaccharide (LPS)-induced gene expression of pro-inflammatory cytokines in an immortalized murine microglial cell line, BV2 cells. RNA profiling (RNA-Seq) was used to analyze the impact of ITI-214 on the BV2 cell transcriptome in the absence and the presence of LPS. ITI-214 was found to regulate classes of genes that are involved in inflammation and cell migration responses to LPS exposure. The gene expression changes seen with ITI-214 treatment were distinct from those elicited by inhibitors of other PDEs with anti-inflammatory activity (e.g., a PDE4 inhibitor), indicating a distinct mechanism of action for PDE1. Functionally, ITI-214 inhibited ADP-induced migration of BV2 cells through a P2Y12-receptor-dependent pathway, possibly due to increases in the extent of cAMP and VASP phosphorylation downstream of receptor activation. Importantly, this effect was recapitulated in P2 rat microglial cells in vitro, indicating that these pathways are active in native microglial cells. These studies are the first to demonstrate that inhibition of PDE1 exerts anti-inflammatory effects through effects on microglia signaling pathways. The ability of PDE1 inhibitors to prevent or dampen excessive inflammatory responses of BV2 cells and microglia provides a basis for exploring their therapeutic utility in the treatment of neurodegenerative diseases associated with increased inflammation and microglia proliferation such as Parkinson's disease and Alzheimer's disease.

    更新日期:2019-11-26
  • Mitochondrial dysfunction in neurons in Friedreich's ataxia
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-23
    Anna Stepanova, Jordi Magrané

    Friedreich's ataxia is a multisystemic genetic disorder within the family of mitochondrial diseases that is characterized by reduced levels of the essential mitochondrial protein frataxin. Based on clinical evidence, the peripheral nervous system is affected early, neuronal dysfunction progresses towards the central nervous system, and other organs (such as heart and pancreas) are affected later. However, little attention has been given to the specific aspects of mitochondria function altered by frataxin depletion in the nervous system. For years, commonly accepted views on mitochondria dysfunction in Friedreich's ataxia stemmed from studies using non-neuronal systems and may not apply to neurons, which have their own bioenergetic needs and present a unique, extensive neurite network. Moreover, the basis of the selective neuronal vulnerability, which primarily affects large sensory neurons in the dorsal root ganglia, large principal neurons in the dentate nuclei of the cerebellum, and pyramidal neurons in the cerebral cortex, remains elusive. In order to identify potential misbeliefs in the field and highlight controversies, we reviewed current knowledge on frataxin expression in different tissues, discussed the molecular function of frataxin, and the consequences of its deficiency for mitochondria structural and functional properties, with a focus on the nervous system.

    更新日期:2019-11-26
  • Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-06
    Zainuddin Quadri, Nicholas Johnson, Frank Zamudio, Abrian Miller, Melinda Peters, Shayna Smeltzer, Jerry B. Hunt, Steven B. Housley, Breanna Brown, Susan Kramer, Christopher M. Norris, Kevin Nash, Edwin Weeber, Daniel C. Lee, Maj-Linda B. Selenica

    Aims The current study utilizes the adeno-associated viral gene transfer system in the CAMKIIα-tTA mouse model to overexpress human wild type TDP-43 (wtTDP-43) and α-synuclein (α-Syn) proteins. The co-existence of these proteins is evident in the pathology of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). Methods The novel bicistronic recombinant adeno-associated virus (rAAV) serotype 9 drives wtTDP-43 and α-Syn expression in the hippocampus via “TetO” CMV promoter. Behavior, electrophysiology, and biochemical and histological assays were used to validate neuropathology. Results We report that overexpression of wtTDP-43 but not α-Syn contributes to hippocampal CA2–specific pyramidal neuronal loss and overall hippocampal atrophy. Further, we report a reduction of hippocampal long-term potentiation and decline in learning and memory performance of wtTDP-43 expressing mice. Elevated wtTDP-43 levels induced selective degeneration of Purkinje cell protein 4 (PCP-4) positive neurons while both wtTDP-43 and α-Syn expression reduced subsets of the glutamate receptor expression in the hippocampus. Conclusions Overall, our findings suggest the significant vulnerability of hippocampal neurons toward elevated wtTDP-43 levels possibly via PCP-4 and GluR-dependent calcium signaling pathways. Further, we report that wtTDP-43 expression induced selective CA2 subfield degeneration, contributing to the deterioration of the hippocampal-dependent cognitive phenotype.

    更新日期:2019-11-07
  • Hippocampal stimulation promotes intracellular Tip60 dynamics with concomitant genome reorganization and synaptic gene activation
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-11-01
    Ashley Karnay, Bhanu Chandra Karisetty, Mariah Beaver, Felice Elefant

    Genomic reorganizations mediating the engagement of target genes to transcription factories (TFs), characterized as specialized nuclear subcompartments enriched in hyperphosphorylated RNA polymerase II (RNAPII) and transcriptional regulators, act as an important layer of control in coordinating efficient gene transcription. However, their presence in hippocampal neurons and potential role in activity-dependent coregulation of genes within the brain remains unclear. Here, we investigate whether the well-characterized role for the histone acetyltransferase (HAT) Tip60 in mediating epigenetic control of inducible neuroplasticity genes involves TF associated chromatin reorganization in the hippocampus. We show that Tip60 shuttles into the nucleus following extracellular stimulation of rat hippocampal neurons with co7ncomitant enhancement of Tip60 binding and activation of specific synaptic plasticity genes. Multicolor three-dimensional (3D) DNA fluorescent in situ hybridization (FISH) reveals that hippocampal stimulation mobilizes these same synaptic plasticity genes and Tip60 to RNAPII-rich TFs. Our data support a model by which external hippocampal stimulation promotes intracellular Tip60 HAT dynamics with concomitant TF associated genome reorganization to initiate Tip60 mediated synaptic gene activation.

    更新日期:2019-11-01
  • Glial mitochondrial function and dysfunction in health and neurodegeneration
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-31
    Kevin McAvoy, Hibiki Kawamata

    Mitochondria play essential metabolic roles in neural cells. Mitochondrial dysfunction has profound effects on the brain. In primary mitochondrial diseases, mutations that impair specific oxidative phosphorylation (OXPHOS) proteins or OXPHOS assembly factors lead to isolated biochemical defects and a heterogeneous group of clinical phenotypes, including mitochondrial encephalopathies. A broader defect of OXPHOS function, due to mutations in proteins involved in mitochondrial DNA maintenance, mitochondrial biogenesis, or mitochondrial tRNAs can also underlie severe mitochondrial encephalopathies. While primary mitochondrial dysfunction causes rare genetic forms of neurological disorders, secondary mitochondrial dysfunction is involved in the pathophysiology of some of the most common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Many studies have investigated mitochondrial function and dysfunction in bulk central nervous system (CNS) tissue. However, the interpretation of these studies has been often complicated by the extreme cellular heterogeneity of the CNS, which includes many different types of neurons and glial cells. Because neurons are especially dependent on OXPHOS for ATP generation, mitochondrial dysfunction is thought to be directly involved in cell autonomous neuronal demise. Despite being metabolically more flexible than neurons, glial mitochondria also play an essential role in the function of the CNS, and have adapted specific metabolic and mitochondrial features to support their diversity of functions. This review analyzes our current understanding and the gaps in knowledge of mitochondrial properties of glia and how they affect neuronal functions, in health and disease.

    更新日期:2019-11-01
  • Fibroblast growth Factor-21 promotes ketone body utilization in neurons through activation of AMP-dependent kinase
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-29
    Yurika Katsu-Jiménez, Alfredo Giménez-Cassina

    Energy supply to the brain is essential to ensure correct neuronal function, and glucose is the main fuel utilized by neurons. In metabolically challenging situations when glucose availability is restricted, brain cells may switch to alternative carbon substrates. This ensures energy supply to preserve the functions of the central nervous system. In this regard, ketone bodies, a by-product of fat metabolism, play a key role. They can replace glucose as the main source of ATP in the brain when glucose availability is very low, such as during fasting, extenuating exercise, or pathological situations such as diabetes. However, the mechanisms through which brain cells reprogram their metabolism are not fully understood. Fibroblast growth factor-21 (FGF21) is an endocrine hormone that contributes to modulate systemic adaptation to fasting, and it is known to regulate ketone body metabolism in peripheral tissues. However, its role in the brain, except for neuroendocrine regions, has not been studied in depth. In this work, we have used a combination of cell biology, biochemistry and extracellular flux analysis to examine the role of FGF21 in neuronal metabolism. We show that FGF21 increases the ability of neurons to utilize ketone bodies in cortical neurons as illustrated by a larger mitochondrial respiratory capacity in the presence of ketone bodies. Finally, we observe that the effect of FGF21 is mediated through a mechanism partly dependent on AMP-dependent kinase (AMPK). We propose that this mechanism could contribute to prepare the brain for fasting, thus preventing metabolic decline.

    更新日期:2019-10-29
  • Role of GPCR signaling and calcium dysregulation in Alzheimer's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-23
    Sushma, Amal Chandra Mondal
    更新日期:2019-10-24
  • Ginkgolic acid promotes autophagy-dependent clearance of intracellular alpha-synuclein aggregates
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-22
    Shamini Vijayakumaran, Yasuko Nakamura, Jeremy M. Henley, Dean L. Pountney

    The accumulation of intracytoplasmic inclusion bodies (Lewy bodies) composed of aggregates of the alpha-synuclein (α-syn) protein is the principal pathological characteristic of Parkinson's disease (PD) and may lead to degeneration of dopaminergic neurons. To date there is no medication that can promote the efficient clearance of these pathological aggregates. In this study, the effect on α-syn aggregate clearance of ginkgolic acid (GA), a natural compound extracted from Ginkgo biloba leaves that inhibits SUMOylation amongst other pathways, was assessed in SH-SY5Y neuroblastoma cells and rat primary cortical neurons. Depolarization of SH-SY5Y neuroblastoma cells and rat primary cortical neurons with KCl was used to induce α-syn aggregate formation. Cells pre-treated with either GA or the related compound, anacardic acid, revealed a significant decrease in intracytoplasmic aggregates immunopositive for α-syn and SUMO-1. An increased frequency of autophagosomes was also detected with both compounds. GA post-treatment 24 h after depolarization also significantly diminished α-syn aggregate bearing cells, indicating the clearance of pre-formed aggregates. Autophagy inhibitors blocked GA-dependent clearance of α-syn aggregates, but not increased autophagosome frequency. Western analysis revealed that the reduction in α-syn aggregate frequency obtained with GA pre-treatment was not accompanied by a significant change in the abundance of SUMO conjugates. The current findings show that GA can promote autophagy-dependent clearance of α-syn aggregates and may have potential in disease modifying therapy.

    更新日期:2019-10-23
  • CBP and p300 coactivators contribute to the maintenance of Isl1 expression by the Onecut transcription factors in embryonic spinal motor neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-21
    Mathilde Toch, Frédéric Clotman

    Onecut transcription factors are required to maintain Islet1 (Isl1) expression in developing spinal motor neurons (MNs), and this process is critical for proper MN differentiation. However, the mechanisms whereby OC stimulate Isl1 expression remain unknown. CREB-binding protein (CBP) and p300 paralogs are transcriptional coactivators that interact with OC proteins in hepatic cells. In the embryonic spinal cord, CBP and p300 play key roles in neurogenesis and MN differentiation. Here, using chromatin immunoprecipitation and in ovo electroporation in chicken spinal cord, we provide evidence that CBP and p300 contribute to the regulation of Isl1 expression by the OC factors in embryonic spinal MNs. CBP and p300 are detected on the CREST2 enhancer of Isl1 where OC factors are also bound. Inhibition of CBP and p300 activity inhibits activation of the CREST2 enhancer and prevents the stimulation of Isl1 expression by the OC factors. These observations suggest that CBP and p300 coactivators cooperate with OC factors to maintain Isl1 expression in postmitotic MNs.

    更新日期:2019-10-22
  • Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-20
    Navneet Ammal Kaidery, Manuj Ahuja, Bobby Thomas
    更新日期:2019-10-21
  • L-type Ca2+ channels and charybdotoxin-sensitive Ca2+-activated K+ channels are required for reduction of GABAergic activity induced by β2-adrenoceptor in the prefrontal cortex
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-10-20
    Wei-Ke Deng, Xing Wang, Hou-Cheng Zhou, Fei Luo

    Whereas β2-adrenoceptor (β2-AR) has been reported to reduce GABAergic activity in the prefrontal cortex (PFC), the underlying cellular and molecular mechanisms have not been completely determined. Here, we showed that β2-AR agonist Clenbuterol (Clen) decreased GABAergic transmission onto PFC layer V/VI pyramidal neurons via a presynaptic mechanism without altering postsynaptic GABA receptors. Clen decreased the action potential firing rate but increased the burst afterhyperpolarization (AHP) amplitude in PFC interneurons. Application of L-type Ca2+ channel or charybdotoxin-sensitive Ca2+-activated K+ channel inhibitors blocked Clen-induced decreases in action potential firing rate, spontaneous inhibitory postsynaptic current (sIPSC) frequency and Clen-induced enhancement of AHP amplitude, suggesting that the effects of Clen involves L-type Ca2+ Channels and charybdotoxin-sensitive Ca2+-activated K+ channels. Our results provide a potential cellular mechanism by which Clen controls GABAergic neuronal activity in PFC.

    更新日期:2019-10-21
  • The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-09-12
    Melissa L. Young, James L. Franklin

    Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aβ accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

    更新日期:2019-09-12
  • Edaravone protects primary-cultured rat cortical neurons from ketamine-induced apoptosis via reducing oxidative stress and activating PI3K/Akt signal pathway
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-09-07
    Qianqian Li, Zhengguo Qiu, Yang Lu, Pan Lu, Jieqiong Wen, Kui Wang, Xijuan Zhao, Rong Li, Hong Zhang, Yan Zhang, Pengyu Jia, Pei Fan, Yuanyuan Zhang, Shuyue Zhang, Haixia Lv, Xinlin Chen, Yong Liu, Pengbo Zhang

    Ketamine caused neuroapoptosis in the development of rat brain, in which oxidative stress play an important role. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, exerts neuroprotective effects in many neurological disease models. Here we investigated whether edaravone protects primary-cultured neurons against ketamine-induced apoptosis and its potential mechanism. Edaravone increased neuronal viability, decreased neuronal apoptosis, increased the ratio of Bcl-2/Bax after ketamine exposure. Edaravone also increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) level in ketamine-exposed neurons. In addition, edaravone increased protein levels of phosphorylated-protein kinase B (p-Akt), phosphorylated-glycogen synthase kinase-3β (p-GSK-3β) and phosphorylated-forkhead box protein O1 (p-FoxO1) in ketamine-exposed neurons. The neuroprotective effects of edaravone were reversed by LY294002, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor. These findings demonstrated that edaravone protected neurons against ketamine-induced apoptosis by diminishing oxidative stress and activating PI3K/Akt signal pathway.

    更新日期:2019-09-07
  • Mechanism of mitochondrial complex I damage in brain ischemia/reperfusion injury. A hypothesis
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-09-05
    Vadim Ten, Alexander Galkin

    The purpose of this review is to integrate available data on the effect of brain ischemia/reperfusion (I/R) on mitochondrial complex I. Complex I is a key component of the mitochondrial respiratory chain and it is the only enzyme responsible for regenerating NAD+ for the maintenance of energy metabolism. The vulnerability of brain complex I to I/R injury has been observed in multiple animal models, but the mechanisms of enzyme damage have not been studied. This review summarizes old and new data on the effect of cerebral I/R on mitochondrial complex I, focusing on a recently discovered mechanism of the enzyme impairment. We found that the loss of the natural cofactor flavin mononucleotide (FMN) by complex I takes place after brain I/R. Reduced FMN dissociates from the enzyme if complex I is maintained under conditions of reverse electron transfer when mitochondria oxidize succinate accumulated during ischemia. The potential role of this process in the development of mitochondrial I/R damage in the brain is discussed.

    更新日期:2019-09-05
  • A disintegrin and metalloproteinase with thrombospondin motifs 2 cleaves and inactivates Reelin in the postnatal cerebral cortex and hippocampus, but not in the cerebellum
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-09-03
    Yuko Yamakage, Michinao Kato, Aya Hongo, Himari Ogino, Keisuke Ishii, Takumi Ishizuka, Takana Kamei, Hitomi Tsuiji, Tomomi Miyamoto, Hisashi Oishi, Takao Kohno, Mitsuharu Hattori

    Reelin plays important roles in regulating neuronal development, modulating synaptic function, and counteracting amyloid β toxicity. A specific proteolytic cleavage (N-t cleavage) of Reelin abolishes its biological activity. We recently identified ADAMTS-3 (a disintegrin and metalloproteinase with thrombospondin motifs 3) as the major N-t cleavage enzyme in the embryonic and early postnatal brain. The contribution of other proteases, particularly in the postnatal brain, has not been demonstrated in vivo. ADAMTS-2, -3 and -14 share similar domain structures and substrate specificity, raising the possibility that ADAMTS-2 and -14 may cleave Reelin. We found that recombinant ADAMTS-2 protein expressed in cultured cell lines cleaves Reelin at the N-t site as efficiently as ADAMTS-3 while recombinant ADAMTS-14 hardly cleaves Reelin. The disintegrin domain is necessary for the Reelin-cleaving activity of ADAMTS-2 and -3. ADAMTS-2 is expressed in the adult brain at approximately the same level as ADAMTS-3. We generated ADAMTS-2 knockout (KO) mice and found that ADAMTS-2 significantly contributes to the N-t cleavage and inactivation of Reelin in the postnatal cerebral cortex and hippocampus, but much less in the cerebellum. Therefore, it was suggested that ADAMTS-2 can be a therapeutic target for adult brain disorders such as schizophrenia and Alzheimer's disease.

    更新日期:2019-09-03
  • Adequate expression of Globin1 is required for development and maintenance of nervous system in Drosophila
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-28
    Nisha, Prerna Aggarwal, Surajit Sarkar

    Neurogenesis is driven by spatially and temporally regulated proliferation of neuronal progenitor cells that generates enormous number of assorted neurons to drive the complex behavior of an organism. Drosophila nervous system provides an advantageous model for identification and elucidation of the functional significance of the novel gene(s) involved in neurogenesis. The present study attempts to investigate the role(s) of globin1 (glob1) in the development and maintenance of the nervous system in Drosophila. It is increasingly clear now that globin genes play important role(s) in the various biological phenomena. The vertebrate neuroglobin has been reported to profoundly express in neuronal tissues and provides neuroprotection. We noted ubiquitous presence of Glob1 in the developing neuronal tissues with enhanced concentration throughout the VNC which comprises of midline cell clusters, which subsequently forms numerous types of progenitor cells and finally differentiate into specific neurons of the nervous system. Ubiquitous or pan-neuronal downregulation of glob1 causes partial lethality and mis-positioning of various neural-progenitor cells present in the embryonic midline cell clusters. Subsequently, profound expression of Glob1 was noted in the outer proliferation center of larval brain and photoreceptor axons of optic stalk. The overall arrangement of photoreceptor axons and stereotype positioning of neuroblast cells present in the central region of the brain were severally affected due to reduced expression of glob1. In addition, such larvae and surviving adults develop significant neuro-muscular disabilities. For the first time, our study suggests a novel role of glob1 in development and maintenance of the nervous system adding a new dimension to the functional significance of the multi-tasking glob1 gene in Drosophila.

    更新日期:2019-08-29
  • Role of fast inhibitory synaptic transmission in neonatal respiratory rhythmogenesis and pattern formation
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-28
    Michael George Zaki Ghali, Sarah Beshay

    Several studies have investigated the general role of chloride-based neurotransmission (GABAA and glycinergic signaling) in respiratory rhythmogenesis and pattern formation. In several brain regions, developmental alterations in these signaling pathways have been shown to be mediated by changes in cation-chloride cotransporter (CC) expression. For instance, CC expression changes over the neonatal period in medullary respiratory nuclei and other brain/spinal cord regions in a manner which decreases the cellular import, and increases the export, of chloride ions, shifting reversal potentials for chloride to progressively more negative values with maturation. In slice preparations of the same, this is related to an excitatory-to-inhibitory shift of GABAA- and glycinergic signaling. In medullary slices, GABAA-/glycinergic signaling in the early neonatal period is excitatory, becoming inhibitory over time. Additionally, blockade of the Na+/K+/2Cl− cotransporter, which imports these ions via secondary active transport, converts excitatory response to inhibitory ones. These effects have not been yet investigated at the individual respiratory-related neuron level to occur in intact (in vivo or in situ) animal preparations, which in contrast to slices, possess normal network connectivity and natural sources of tonic drive. Developmental changes in medullary respiratory circuitry may contribute to critical periods, during which there exist increased risk for perinatal respiratory disturbances of central, obstructive, or hypoxia/hypercapnia-induced origin, including the sudden infant death syndrome. Thus, better characterizing the neurochemical maturation of the central respiratory network will enhance our understanding of these conditions, which will facilitate development of targeted therapies for respiratory disturbances in neonates and infants.

    更新日期:2019-08-29
  • PlexinD1 and Sema3E determine laminar positioning of heterotopically projecting callosal neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-24
    Theodora Velona, Mike Altounian, Micaela Roque, Mélanie Hocine, Anaïs Bellon, Carlos Garcia Briz, Pascal Salin, Marta Nieto, Sophie Chauvet, Fanny Mann

    The corpus callosum is the largest bundle of commissural fibres that transfer information between the two cerebral hemispheres. Callosal projection neurons (CPNs) are a diverse population of pyramidal neurons within the neocortex that mainly interconnect homotopic regions of the opposite cortices. Nevertheless, some CPNs are involved in heterotopic projections between distinct cortical areas or to subcortical regions such as the striatum. In this study, we showed that the axon guidance receptor PlexinD1 is expressed by a large proportion of heterotopically projecting CPNs in layer 5A of the primary somatosensory (S1) and motor (M1) areas. Retrograde tracing of M1 CPNs projecting to the contralateral striatum revealed the presence of ectopic neurons aberrantly located in layers 2/3 of Plxnd1 and Sema3e mutant cortices. These results showed that Sema3E/PlexinD1 signalling controls the laminar distribution of heterotopically projecting CPNs.

    更新日期:2019-08-25
  • TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-21
    Ju Gao, Luwen Wang, Tingxiang Yan, George Perry, Xinglong Wang

    Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlining TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.

    更新日期:2019-08-22
  • Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-15
    Khalil Saadipour, Alexia Tiberi, Sylvia Lomardo, Elena Grajales, Laura Montroull, Noralyn B. Mañucat-Tan, John LaFrancois, Michael Cammer, Paul M. Mathews, Helen E. Scharfman, Francesca-Fang Liao, Wilma J. Friedman, Xin-Fu Zhou, Giueseppina Tesco, Moses V. Chao

    BACE1 is a transmembrane aspartic protease that cleaves various substrates and it is required for normal brain function. BACE1 expression is high during early development, but it is reduced in adulthood. Under conditions of stress and injury, BACE1 levels are increased; however, the underlying mechanisms that drive BACE1 elevation are not well understood. One mechanism associated with brain injury is the activation of injurious p75 neurotrophin receptor (p75), which can trigger pathological signals. Here we report that within 72 h after controlled cortical impact (CCI) or laser injury, BACE1 and p75 are increased and tightly co-expressed in cortical neurons of mouse brain. Additionally, BACE1 is not up-regulated in p75 null mice in response to focal cortical injury, while p75 over-expression results in BACE1 augmentation in HEK-293 and SY5Y cell lines. A luciferase assay conducted in SY5Y cell line revealed that BACE1 expression is regulated at the transcriptional level in response to p75 transfection. Interestingly, this effect does not appear to be dependent upon p75 ligands including mature and pro-neurotrophins. In addition, BACE1 activity on amyloid precursor protein (APP) is enhanced in SY5Y-APP cells transfected with a p75 construct. Lastly, we found that the activation of c-jun n-terminal kinase (JNK) by p75 contributes to BACE1 up-regulation. This study explores how two injury-induced molecules are intimately connected and suggests a potential link between p75 signaling and the expression of BACE1 after brain injury.

    更新日期:2019-08-15
  • Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer's disease iPSC-derived neurons and mice
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-08-02
    Carlo Cusulin, Isabelle Wells, Solveig Badillo, Gonzalo Christian Duran Pacheco, Karlheinz Baumann, Christoph Patsch

    In drug discovery, as well as in the study of disease biology, it is fundamental to develop models that recapitulate aspects of a disorder, in order to understand the pathology and test therapeutic approaches. Patient-derived induced pluripotent stem cells (iPSCs) offer the potential of obtaining tissue-specific cells with a given human genotype. Here we derived neural cultures from Alzheimer's disease patient iPSCs and characterized their response to three classes of compounds that reduce the production of Aβ42, a major driving force of this pathology. We characterized their effect on the cells, looking at Tau proteostasis and gene expression changes by RNAseq. β-secretase inhibitor and γ-secretase modulators left the transcriptional balance of the cells virtually unaffected, while γ-secretase inhibitors caused drastic gene expression changes due to Notch inhibition. We observed similar effects in vivo, treating mice with the same compound classes. Our results show that β-secretase inhibitors and γ-secretase modulators are attractive candidates for modulating Aβ production in Alzheimer's disease. Moreover, we demonstrate that the response to compounds obtained with iPSC-derived neurons is similar to the one observable in vivo.

    更新日期:2019-08-02
  • Evoked potentials as a translatable biomarker to track functional remyelination
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-07-26
    Brandon J. Farley, Elena Morozova, Jessica Dion, Bin Wang, Brian D. Harvey, Davide Gianni, Brian Wipke, Diego Cadavid, Marion Wittmann, Mihaly Hajos

    Enhancing remyelination is a key therapeutic strategy for demyelinating diseases such as multiple sclerosis. To achieve this goal, a central challenge is being able to quantitatively and longitudinally track functional remyelination, especially with translatable biomarkers that can be performed in both preclinical models and in the clinic. We developed the methodology to stably measure multi-modal sensory evoked potentials from the skull surface over the course of months in individual mice and applied it to a genetic mouse model of oligodendrocyte ablation and demyelination. We found that auditory and somatosensory evoked potential latencies reliably increased over time during the early phase of the model and recovered spontaneously and almost completely during a later phase. Histological examination supported the interpretation that the evoked potential latency changes dynamically reflect changes in CNS myelination. Specifically, we found reduction of myelination in corresponding brain regions at the time that sensory evoked potentials were maximally impacted. Importantly, we also found that myelination levels recovered when evoked potential latencies recovered. Other changes known to associate with demyelination were also observed at the time of delayed evoked potentials, including the emergence of white matter vacuoles and increased markers for activated microglia and macrophages; these changes also fully reversed by the time that evoked potentials recovered. Our results support the hypothesis that skull-surface recorded evoked potential latencies can dynamically track CNS myelination changes. The methods developed here allow for longitudinally tracking functional myelination changes in vivo in preclinical rodent models with a quantitative biomarker that can also be applied clinically and will facilitate translational development of CNS remyelinating therapies.

    更新日期:2019-07-27
  • PLD1 promotes dendritic spine morphogenesis via activating PKD1
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-07-26
    Wen-Qi Li, Li-Da Luo, Zhi-Wen Hu, Tian-Jie Lyu, Cheng Cen, Yun Wang

    Dendritic spines on the dendrites of pyramidal neurons are one of the most important components for excitatory synapses, where excitatory information exchanges and integrates. The defects of dendritic spine development have been closely connected with many nervous system diseases including autism, intellectual disability and so forth. Based on our previous studies, we here report a new functional signaling link between phospholipase D1 (PLD1) and protein kinase D1 (PKD1) in dendritic spine morphogenesis. Coimmunoprecipitation assays showed that PLD1 associates with PKD1. A series of knocking down and rescuing experiments demonstrated that PLD1 acts upstream of PKD1 in positively regulating dendritic spine morphogenesis. Using PLD1 inhibitor, we found that PLD1 activates PKD1 to promote dendritic spine morphogenesis. Thus, we further reveal the roles of the two different enzymes in neuronal development.

    更新日期:2019-07-27
  • Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-07-02
    Chaitanya Chakravarthi Gali, Elham Fanaee-Danesh, Martina Zandl-Lang, Nicole Maria Albrecher, Carmen Tam-Amersdorfer, Anika Stracke, Vinay Sachdev, Florian Reichmann, Yidan Sun, Afrim Avdili, Marielies Reiter, Dagmar Kratky, Peter Holzer, Achim Lass, Karunya K. Kandimalla, Ute Panzenboeck
    更新日期:2019-07-03
  • Modulating proteoglycan receptor PTPσ using intracellular sigma peptide improves remyelination and functional recovery in mice with demyelinated optic chiasm
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-07-02
    Parvin Niknam, Mohammad Reza Raoufy, Yaghoub Fatholahi, Mohammad Javan

    Multiple sclerosis (MS) is an autoimmune disease characterized by myelin and axonal damage in the central nervous system (CNS). Glial scar which is a hallmark of MS contains repair inhibitory molecules including chondroitin sulfate proteoglycans (CSPGs). CSPGs inhibit repair of damaged area through various receptors including protein tyrosine phosphatase sigma (PTPσ). In the current study we use intracellular sigma peptide (ISP), an inhibitor of PTPσ signaling, in LPC-induced focal demyelination of mouse optic chiasm. ISP treatment resulted in decreased demyelination, reduced astrogliosis, and increased newly generated oligodendrocytes which subsequently led to enhanced remyelination. Analyzing of electrophysiological (as performed by visual evoked potential recording) and behavioral (performed by visual cliff test) outcomes showed that ISP-treatment improved the integrity of optic pathway as well as the visual acuity. When ISP was administrated only during the repair phase, histological, electrophysiological and behavioral studies showed its regenerative effect. Our results demonstrated the possibility of using ISP as a new strategy to inhibit PTPσ for myelin protection, myelin repair in demyelinated axons, and functional neural pathway conductivity restoration in patients suffering from MS.

    更新日期:2019-07-03
  • Mitochondrial dynamics and transport in Alzheimer's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-16
    Padraig J. Flannery, Eugenia Trushina

    Mitochondrial dysfunction is now recognized as a contributing factor to the early pathology of multiple human conditions including neurodegenerative diseases. Mitochondria are signaling organelles with a multitude of functions ranging from energy production to a regulation of cellular metabolism, energy homeostasis, stress response, and cell fate. The success of these complex processes critically depends on the fidelity of mitochondrial dynamics that include the ability of mitochondria to change shape and location in the cell, which is essential for the maintenance of proper function and quality control, particularly in polarized cells such as neurons. This review highlights several aspects of alterations in mitochondrial dynamics in Alzheimer's disease, which may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative approach to failed amyloid-directed interventions.

    更新日期:2019-06-16
  • PRRT1 regulates basal and plasticity-induced AMPA receptor trafficking
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-16
    Eva Troyano-Rodriguez, Shivani Mann, Raja Ullah, Mohiuddin Ahmad

    AMPA-type glutamate receptors (AMPAR) are one of the principal mediators of fast excitatory synaptic transmission in the brain. These receptors associate with multiple integral membrane proteins which influence their trafficking and channel properties. Proline-rich transmembrane protein 1 (PRRT1) is a membrane protein and an understudied component of native AMPAR complexes. In order to understand the regulation of AMPARs by PRRT1, we have performed electrophysiological and biochemical investigations on acute hippocampal slices derived from PRRT1 knockout mice. Our results show that PRRT1 controls the levels of AMPARs at the cell surface, though it is dispensable for synaptic transmission. PRRT1 has differential effects on the stability of AMPAR GluA1 subunit phosphorylated at S845 and at S831, two residues at which the phosphorylation status has major influences on receptor trafficking. Furthermore, PRRT1 is required for NMDA receptor-dependent long-term depression (LTD) and proper NMDA-induced AMPAR trafficking. These findings position PRRT1 as an important regulator of AMPAR stabilization and trafficking in different subcellular pools under basal conditions and during synaptic plasticity.

    更新日期:2019-06-16
  • A novel bungarotoxin binding site-tagged construct reveals MAPK-dependent Kv4.2 trafficking
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-15
    G. Travis Tabor, Jung M. Park, Jonathan G. Murphy, Jia-Hua Hu, Dax A. Hoffman

    Kv4.2 voltage-gated K+ channel subunits, the primary source of the somatodendritic A-type K+ current in CA1 pyramidal neurons of the hippocampus, play important roles in regulating dendritic excitability and plasticity. To better study the trafficking and subcellular distribution of Kv4.2, we created and characterized a novel Kv4.2 construct encoding a bungarotoxin binding site in the extracellular S3–S4 linker region of the α-subunit. When expressed, this construct can be visualized in living cells after staining with rhodamine-conjugated bungarotoxin. We validated the utility of this construct by visualizing the spontaneous internalization and insertion of Kv4.2 in HEK 293T cells. We further report that Kv4.2 colocalized with several endosome markers in HEK 293T cells. In addition, Kv4.2 internalization is significantly impaired by mitogen-activated protein kinase (MAPK) inhibitors in transfected primary hippocampal neurons. Therefore, this newly developed BBS-Kv4.2 construct provides a novel and powerful tool for studying surface Kv4.2 channel localization and trafficking.

    更新日期:2019-06-16
  • BDNF elevates the axonal levels of hnRNPs Q and R in cultured rat cortical neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-14
    Hui-Wen Chung, Ju-Chen Weng, Chih-En King, Chih-Fan Chuang, Wei-Yuan Chow, Yen-Chung Chang

    Local translation plays important roles in the maintenance and various functions of axons, and dysfunctions of local translation in axons are implicated in various neurological diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA binding proteins with multiple functions in RNA metabolism. Here, we identified 20 hnRNPs in the axons of cultured rat cortical neurons by interrogating published axon mass spectrometric databases with rat protein databases. Among those identified in axons are highly related hnRNPs Q and R. RT-PCR analysis indicated that axons also contained low levels of hnRNPs Q and R mRNAs. We further found that BDNF treatments raised the levels of hnRNPs Q and R proteins in whole neurons and axons. BDNF also increased the level of poly(A) RNA as well as the proportion of poly(A) RNA granules containing hnRNPs Q and R in the axon. However, following severing the connection between the cell bodies and axons, BDNF did not affect the levels of hnRNPs Q and R, the content of poly(A) RNA, or the colocalization of poly(A) RNA and hnRNPs Q and R in the axon any more, although BDNF still stimulated the local translation in severed axons as it did in intact axons. The results are consistent with that BDNF enhances the axonal transport of RNA granules. The results further suggest that hnRNPs Q and R play a role in the mechanism underlying the enhancement of axonal RNA transport by BDNF.

    更新日期:2019-06-14
  • Activation of WNT and CREB signaling pathways in human neuronal cells in response to the Omega-3 fatty acid docosahexaenoic acid (DHA)
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-14
    Wen-Ning Zhao, Norma K. Hylton, Jennifer Wang, Peter S. Chindavong, Begum Alural, Iren Kurtser, Aravind Subramanian, Ralph Mazitschek, Roy H. Perlis, Stephen J. Haggarty
    更新日期:2019-06-14
  • Acrolein-mediated alpha-synuclein pathology involvement in the early post-injury pathogenesis of mild blast-induced Parkinsonian neurodegeneration
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-12
    Glen Acosta, Nicholas Race, Seth Herr, Joseph Fernandez, Jonathan Tang, Edmond Rogers, Riyi Shi

    Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons. Using an established bTBI rat model, we evaluated the changes of α-synuclein and tyrosine hydroxylase (TH), known hallmarks of PD, and acrolein, a reactive aldehyde and marker of oxidative stress, with the aim of revealing key pathways leading to PD post-bTBI. Indicated in both animal models of PD and TBI, acrolein is likely a point of pathogenic convergence. Here we show that after a single mild bTBI, acrolein is elevated up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. Acrolein elevation is accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. We further show that acrolein can directly modify and oligomerize α-synuclein in vitro. Taken together, our data suggests acrolein likely plays an important role in inducing PD pathology following bTBI by encouraging α-synuclein aggregation. These results are expected to advance our understanding of the long-term post-bTBI pathological changes leading to the development of PD, and suggest intervention targets to curtail such pathology.

    更新日期:2019-06-12
  • 1H NMR profiling of the 6-OHDA parkinsonian rat brain reveals metabolic alterations and signs of recovery after N-acetylcysteine treatment
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-12
    Ana Virel, Ilona Dudka, Rutger Laterveer, Sara af Bjerkén

    Parkinson's disease is the second most common neurodegenerative disease caused by degeneration of dopamine neurons in the substantia nigra. The origin and causes of dopamine neurodegeneration in Parkinson's disease are not well understood but oxidative stress may play an important role in its onset. Much effort has been dedicated to find biomarkers indicative of oxidative stress and neurodegenerative processes in parkinsonian brains. By using 1H NMR (nuclear magnetic resonance) to identify and quantify key metabolites, it is now possible to elucidate the metabolic pathways affected by pathological conditions like neurodegeneration. The metabolic disturbances in the 6-hydroxydopamine (6-OHDA) hemiparkinsonian rat model were monitored and the nature and size of these metabolic alterations were analyzed. The results indicate that a unilateral injection of 6-OHDA into the striatum causes metabolic changes that not only affect the injected hemisphere but also the contralateral, non-lesioned side. We could clearly identify specific metabolic pathways that were affected, which were mostly related with oxidative stress and neurotransmission. In addition, a partial metabolic recovery by carrying out an antioxidant treatment with N-acetylcysteine (NAC) was observable.

    更新日期:2019-06-12
  • mir-234 controls neuropeptide release at the Caenorhabditis elegans neuromuscular junction
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-12
    Goda Snieckute, Oguzhan Baltaci, Haowen Liu, Lei Li, Zhitao Hu, Roger Pocock

    miR-137 is a highly conserved microRNA (miRNA) that is associated with the control of brain function and the etiology of psychiatric disorders including schizophrenia and bipolar disorder. The Caenorhabditis elegans genome encodes a single miR-137 ortholog called mir-234, the function of which is unknown. Here we show that mir-234 is expressed in a subset of sensory, motor and interneurons in C. elegans. Using a mir-234 deletion strain, we systematically examined the development and function of these neurons in addition to global C. elegans behaviors. We were however unable to detect phenotypes associated with loss of mir-234, possibly due to genetic redundancy. To circumvent this issue, we overexpressed mir-234 in mir-234-expressing neurons to uncover possible phenotypes. We found that mir-234-overexpression endows resistance to the acetylcholinesterase inhibitor aldicarb, suggesting modification of neuromuscular junction (NMJ) function. Further analysis revealed that mir-234 controls neuropeptide levels, therefore positing a cause of NMJ dysfunction. Together, our data suggest that mir-234 functions to control the expression of target genes that are important for neuropeptide maturation and/or transport in C. elegans. Significance statement The miR-137 family of miRNAs is linked to the control of brain function in humans. Defective regulation of miR-137 is associated with psychiatric disorders that include schizophrenia and bipolar disorder. Previous studies have revealed that miR-137 is required for the development of dendrites and for controlling the release of fast-acting neurotransmitters. Here, we analyzed the function a miR-137 family member (called mir-234) in the nematode animal model using anatomical, behavioral, electrophysiological and neuropeptide analysis. We reveal for the first time that mir-234/miR-137 is required for the release of slow-acting neuropeptides, which may also be of relevance for controlling human brain function.

    更新日期:2019-06-12
  • Embryonic and postnatal development of mouse olfactory tubercle
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-06-11
    Eduardo Martin-Lopez, Christine Xu, Teresa Liberia, Sarah J. Meller, Charles A. Greer

    The olfactory tubercle (OT) is located in the ventral-medial region of the brain where it receives primary input from olfactory bulb (OB) projection neurons and processes olfactory behaviors related to motivation, hedonics of smell and sexual encounters. The OT is part of the dopamine reward system that shares characteristics with the striatum. Together with the nucleus accumbens, the OT has been referred to as the “ventral striatum”. However, despite its functional importance little is known about the embryonic development of the OT and the phenotypic properties of the OT cells. Here, using thymidine analogs, we establish that mouse OT neurogenesis occurs predominantly between E11-E15 in a lateral-to-medial gradient. Then, using a piggyBac multicolor technique we characterized the migratory route of OT neuroblasts from their embryonic point of origin. Following neurogenesis in the ventral lateral ganglionic eminence (vLGE), neuroblasts destined for the OT followed a dorsal-ventral pathway we named “ventral migratory course" (VMC). Upon reaching the nascent OT, neurons established a prototypical laminar distribution that was determined, in part, by the progenitor cell of origin. A phenotypic analysis of OT neuroblasts using a single-color piggyBac technique, showed that OT shared the molecular specification of striatal neurons. In addition to primary afferent input from the OB, the OT also receives a robust dopaminergic input from ventral tegmentum (Ikemoto, 2007). We used tyrosine hydroxylase (TH) expression as a proxy for dopaminergic innervation and showed that TH onset occurs at E13 and progressively increased until postnatal stages following an ‘inside-out’ pattern. Postnatally, we established the myelination in the OT occurring between P7 and P14, as shown with CNPase staining, and we characterized the cellular phenotypes populating the OT by immunohistochemistry. Collectively, this work provides the first detailed analysis of the developmental and maturation processes occurring in mouse OT, and demonstrates the striatal nature of the OT as part of the ventral striatum (vST).

    更新日期:2019-06-11
  • Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-05-31
    Toshihiko Shirafuji, Haruo Shimazaki, Tatsuhiro Miyagi, Takehiko Ueyama, Naoko Adachi, Shigeru Tanaka, Izumi Hide, Naoaki Saito, Norio Sakai

    Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia with myoclonus, dystonia, spasticity, and rigidity. Although missense mutations and a deletion mutation have been found in the protein kinase C gamma (PRKCG) gene encoding protein kinase C γ (PKCγ) in SCA14 families, a nonsense mutation has not been reported. The patho-mechanisms underlying SCA14 remain poorly understood. However, gain-of-function mechanisms and loss-of-function mechanisms, but not dominant negative mechanisms, were reported the patho-mechanism of SCA14. We identified the c.226C>T mutation of PRKCG, which caused the p.R76X in PKCγ by whole-exome sequencing in patients presenting cerebellar atrophy with cognitive and hearing impairment. To investigate the patho-mechanism of our case, we studied aggregation formation, cell death, and PKC inhibitory effect by confocal microscopy, western blotting with cleaved caspase 3, and pSer PKC motif antibodies, respectively. PKCγ(R76X)-GFP have aggregations the same as wild-type (WT) PKCγ-GFP. The PKCγ(R76X)-GFP inhibited PKC phosphorylation activity more than GFP alone. It also induced more apoptosis in COS7 and SH-SY5Y cells compared to WT-PKCγ-GFP and GFP. We first reported SCA14 patients with p.R76X in PKCγ who have cerebellar atrophy with cognitive and hearing impairment. Our results suggest that a dominant negative mechanism due to truncated peptides produced by p.R76X may be at least partially responsible for the cerebellar atrophy.

    更新日期:2019-06-03
  • Hippocampal sub-regional differences in the microRNA response to forebrain ischemia
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-05-23
    Oiva Arvola, Georgia Kaidonis, Lijun Xu, Brian Griffiths, Creed M. Stary

    Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.

    更新日期:2019-05-23
  • Klotho deficiency affects the spine morphology and network synchronization of neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-04-13
    Hai T. Vo, Mary L. Phillips, Jeremy H. Herskowitz, Gwendalyn D. King

    Klotho-deficient mice rapidly develop cognitive impairment and show some evidence of the onset of neurodegeneration. However, it is impossible to investigate the long-term consequences on the brain because of the dramatic shortening of lifespan caused by systemic klotho deficiency. As klotho expression is downregulated with advancing organismal age, understanding the mechanisms of klotho action is important for developing novel strategies to support healthy brain aging. Previously, we reported that klotho-deficient mice show enhanced long-term potentiation prior to the onset of cognitive impairment. To inform this unusual phenotype, herein, we examined neuronal structure and in vitro synaptic function. Our results indicate that klotho deficiency causes the population of dendritic spines to shift towards increased head diameter and decreased length consistent with mature, mushroom type spines. Multi-electrode array recordings from klotho-deficient neurons show increased synchronous firing and activity changes reflective of increased neuronal network activity. Supplementation of the neuronal growth media with recombinant shed klotho corrected some but not all of the activity changes caused by klotho deficiency. Last, in vivo we found that klotho-deficient mice have a decreased latency to induced seizure activity. Together these data show that klotho-deficient memory impairments are underpinned by structural and functional changes that may preclude ongoing normal cognition.

    更新日期:2019-05-17
  • Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-05-04
    Kelly A. Jones, Michiko Sumiya, Kevin M. Woolfrey, Deepak P. Srivastava, Peter Penzes

    EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2−/−) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2−/− mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2−/− mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.

    更新日期:2019-05-17
  • Cross talk between SOD1 and the mitochondrial UPR in cancer and neurodegeneration
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-04-24
    Maria Gomez, Doris Germain

    The mitochondrial unfolded protein response (UPRmt) is rapidly gaining attention. While the CHOP (ATF4/5) axis of the UPRmt was the first to be described, other axes have subsequently been reported. Validation of this complex pathway in C. elegans has been extensively studied. However, validation of the UPRmt in mouse models of disease known to implicate mitochondrial reprogramming or dysfunction, such as cancer and neurodegeneration, respectively, is only beginning to emerge. This review summarizes recent findings and highlights the major role of the superoxide dismutase SOD1 in the communication between the mitochondria and the nucleus in these settings. While SOD1 has mostly been studied in the context of familial amyotrophic lateral sclerosis (fALS), recent studies suggest that SOD1 may be a potentially important mediator of the UPRmt and converge to emphasize an increasingly vital role of SOD1 as a therapeutic target in cancer.

    更新日期:2019-05-17
  • Exposing immature hippocampal neurons to excitotoxins reveals distinct transcriptome and protein regulation with induction of common survival signaling pathways
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-05-11
    L.K. Friedman, N. Osei-tutu, B. Zhang

    Early life traumas lead to neuroprotection by preconditioning mechanisms. To determine which genes and pathways are most likely involved in specific adaptive effects, immature hippocampal cultures were exposed to a single high dose of glutamate (250 μM), NMDA (100 μM), or KA (300 μM) for 48 h (5–7 DIV) based on our prior “two hit” in vitro model of preconditioning. Transcriptome profiling and immunocytochemistry of gene candidates were performed 7 days later when cultured neurons mature (14 DIV). Many genes were up- and down- regulated involving distinct Ca2+-binding protein families, G-coupled proteins, various growth factors, synaptic vesicle docking factors, certain neurotransmitter receptors, heat shock, oxidative stress, and certain anti-apoptotic Bcl-2 gene members that influence neuronal survival. Immunohistochemistry showed a marked decrease in the number of Calb1 and Calm2 positive neurons following NMDA but not after glutamate exposure whereas ryanodine and Cav1.2 voltage gated channel expression was less affected. Survivors had marked increases in Calm2 immunostaining; however, high-density neural clusters observed in controls, were depleted after NMDA and partly diminished after glutamate. While NR1 mRNA expression was decreased in the microarray, specific antibodies revealed selective loss of the NR1 C1 splice variant. Calm2 which can inactivate NMDA receptors by binding to C1 but not C2 regions of its NR1 subunit suggests that loss of the C1 splice variant will reduce co-regulation with Calm2 and alter NR1 trafficking, phosphorylation, and NMDA currents following early life NMDA exposure. A dramatic reduction in the density of GABAAα5 and GABAB receptor expressing neurons was observed after NMDA exposure but immunodensity measurements were unchanged as was the expression of the GABA synthesizing enzyme, GAD, suggesting that fast inhibitory neurotransmission and response to benzodiazepines and GABAB-mediated IPSPs may be preserved in matured survivors. Selective upregulation of Chat and CNRIP was detected after glutamate treatment suggesting this condition would decrease cholinergic and excitatory neurotransmission by decreasing Ach content and CB1 interacting protein function. This decrease likely contributes to memory and attention tasks deficits that follow a single early neurological insult. Diverse changes that follow overactivation of excitatory networks of immature neurons appear long-lasting or permanent and are expected to have profound effects on network function and adaptive responses to further insult.

    更新日期:2019-05-17
  • An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-04-04
    A. Foster, D. Scott, R. Layfield, S.L. Rea

    Elevated oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In response to oxidative stress, the Nrf2 transcription factor activates protective antioxidant genes. A critical regulator of Nrf2 is the inhibitory protein Keap1, which mediates Nrf2 degradation. In response to cellular stress an interaction between Keap1 and SQSTM1/p62 (p62), a signalling adaptor protein, allows for increased Nrf2 signalling as it escapes degradation. Mutations in SQSTM1 (encoding p62) are linked with ALS-FTLD. Previously, two ALS-FTLD-associated p62 mutant proteins within the Keap1 interacting region (KIR) of p62 were found to be associated with decreased Keap1-p62 binding and Nrf2 activation. Here we report that a non-KIR domain FTLD-associated variant of p62 (p.R110C), affecting a residue close to the N-terminal PB1 oligomerisation domain, also reduces Keap1-p62 binding in cellulo and thereby reduces Nrf2 activity in reporter assays. Further, we observed that expression of p.R110C increased NF-κB activation compared with wild type p62. Altered signalling appeared to be linked with reduced phosphorylation of p62 at Serine residues −349 and −403. Our results confirm that ALS-FTLD mutations affecting multiple domains of p62 result in a reduced stress response, suggesting that altered stress signalling may directly contribute to the pathology of some ALS-FTLD cases.

    更新日期:2019-05-17
  • Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-02-13
    Mariana Oliveira Mendes, Alexandra Isabel Rosa, Andreia Neves Carvalho, Maria João Nunes, Pedro Dionísio, Elsa Rodrigues, Daniela Costa, Sara Duarte-Silva, Patrícia Maciel, Cecília Maria Pereira Rodrigues, Maria João Gama, Margarida Castro-Caldas

    Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

    更新日期:2019-03-13
  • Taxifolin protects neurons against ischemic injury in vitro via the activation of antioxidant systems and signal transduction pathways of GABAergic neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-02-15
    M.V. Turovskaya, S.G. Gaidin, V.N. Mal'tseva, V.P. Zinchenko, E.A. Turovsky

    Cerebral blood flow disturbances lead to the massive death of brain cells. The death of >80% of cells is observed in hippocampal cell cultures after 40 min of oxygen and glucose deprivation (ischemia-like conditions, OGD). However, there are some populations of GABAergic neurons which are characterized by increased vulnerability to oxygen-glucose deprivation conditions. Using fluorescent microscopy, immunocytochemical assay, vitality tests and PCR-analysis, we have shown that population of GABAergic neurons are characterized by a different (faster) Ca2+ dynamics in response to OGD and increased basal ROS production under OGD conditions. A plant flavonoid taxifolin inhibited an excessive ROS production and an irreversible cytosolic Ca2+ concentration increase in GABAergic neurons, preventing the death of these neurons and further excitation of a neuronal network; neuroprotective effect of taxifolin increased after incubation of 24 h and correlated with increased expression of antiapoptocic and antioxidant genes Stat3 Nrf-2 Bcl-2, Bcl-xL, Ikk2, and genes coding for AMPA and kainate receptor subunits; in addition, taxifolin decreased expression of prooxidant enzyme NOS and proinflammatory cytokine IL-1β.

    更新日期:2019-03-13
  • Small molecules as therapeutic drugs for Alzheimer's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-03-12
    Darryll M.A. Oliver, P. Hemachandra Reddy

    Mitochondrial dysfunction is a central protagonist of Alzheimer's disease (AD) pathogenesis. Mitochondrial dysfunction stems from various factors including mitochondrial DNA damage and oxidative stress from reactive oxygen species, membrane and ionic gradient destabilization, and interaction with toxic proteins such as amyloid beta (Aβ). Therapeutic drugs such as cholinesterase and glutamate inhibitors have proven to improve synaptic neurotransmitters, but do not address mitochondrial dysfunction. Researchers have demonstrated that oxidative damage may be reduced by increasing endogenous antioxidants, and/or increasing exogenous antioxidants such as vitamin C & E, beta-carotene and glutathione. Nonetheless, as AD pathology intensifies, endogenous antioxidants are overwhelmed, and exogenous antioxidants are unable to reach neuronal mitochondria as they are blocked by the blood brain barrier. Current therapeutic methods however include novel usage of lipophilic phosphonium cation bound to antioxidants, to effect neuronal mitochondria targeted activity. Mitochondria targeted MitoQ, MitoVitE, MitoTempo, MitoPBN and MCAT concentrate within mitochondria where they scavenge free-radicals, and augment mitochondrial dysfunction. Additional molecules include Szeto-Schiller (SS) peptides which target stability of the inner mitochondrial membrane, and DDQ molecule capable of improving bioenergetics and reduce mitochondrial fragmentation. This article discusses advantages and disadvantages of small molecules, their ability to mitigate Aβ induced damage, and ability to ameliorate synaptic dysfunction and cognitive loss.

    更新日期:2019-03-13
  • Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) – Candidate mechanism for UCB-induced neuromodulation and neurotoxicity
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-03-12
    Walid Albanna, Jan Niklas Lüke, Gerrit Alexander Schubert, Maxine Dibué-Adjei, Konstantin Kotliar, Jürgen Hescheler, Hans Clusmann, Hans-Jakob Steiger, Daniel Hänggi, Marcel A. Kamp, Toni Schneider, Felix Neumaier

    Elevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCB:albumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3 + β3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/A = 0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/A = 1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function. Acutely administered UCB (U/A = 0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Cav2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Cav2.3 channels. Together, these findings show that UCB affects cloned and native Cav2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.

    更新日期:2019-03-13
  • Growth and excitability at synapsin II deficient hippocampal neurons
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-03-09
    Heidi Matos, Raymond Quiles, Rodrigo Andrade, Maria Bykhovskaia

    Synapsins are neuronal phosphoproteins that fine-tune synaptic transmission and suppress seizure activity. Synapsin II (SynII) deletion produces epileptic seizures and overexcitability in neuronal networks. Early studies in primary neuronal cultures have shown that SynII deletion results in a delay in synapse formation. More recent studies at hippocampal slices have revealed increased spontaneous activity in SynII knockout (SynII(−)) mice. To reconcile these observations, we systematically re-examined synaptic transmission, synapse formation, and neurite growth in primary hippocampal neuronal cultures. We find that spontaneous glutamatergic synaptic activity was suppressed in SynII(−) neurons during the initial developmental epoch (7 days in vitro, DIV) but was enhanced at later times (12 and18 DIV). The density of synapses, transmission between connected pairs of neurons, and the number of docked synaptic vesicles were not affected by SynII deletion. However, we found that neurite outgrowth in SynII(−) neurons was suppressed during the initial developmental epoch (7 DIV) but enhanced at subsequent developmental stages (12 and18 DIV). This finding can account for the observed effect of SynII deletion on synaptic activity. To test whether the observed phenotype resulted directly from the deletion of SynII we expressed SynII in SynII(−) cultures using an adeno-associated virus (AAV). Expression of SynII at 2 DIV rescued the SynII deletion-dependent alterations in both synaptic activity and neuronal growth. To test whether the increased neurite outgrowth in SynII(−) observed at DIV 12 and18 represents an overcompensation for the initial developmental delay or results directly from SynII deletion we performed “late expression” experiments, transfecting SynII(−) cultures with AAV at 7 DIV. The late SynII expression suppressed neurite outgrowth at 12 and 18 DIV to the levels observed in control neurons, suggesting that these phenotypes directly depend on SynII. These results reveal a novel developmentally regulated role for SynII function in the control of neurite growth.

    更新日期:2019-03-13
  • Fluid and imaging biomarkers for Huntington's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-02-23
    Paul Zeun, Rachael I. Scahill, Sarah J. Tabrizi, Edward J. Wild

    Huntington's disease is a chronic progressive neurodegenerative condition for which there is no disease-modifying treatment. The known genetic cause of Huntington's disease makes it possible to identify individuals destined to develop the disease and instigate treatments before the onset of symptoms. Multiple trials are already underway that target the cause of HD, yet clinical measures are often insensitive to change over typical clinical trial duration. Robust biomarkers of drug target engagement, disease severity and progression are required to evaluate the efficacy of treatments and concerted efforts are underway to achieve this. Biofluid biomarkers have potential advantages of direct quantification of biological processes at the molecular level, whilst imaging biomarkers can quantify related changes at a structural level in the brain. The most robust biofluid and imaging biomarkers can offer complementary information, providing a more comprehensive evaluation of disease stage and progression to inform clinical trial design and endpoints.

    更新日期:2019-03-13
  • Synaptic vesicle protein 2A as a potential biomarker in synaptopathies
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2019-02-20
    Kerstin Heurling, Nicholas J. Ashton, Antoine Leuzy, Eduardo R. Zimmer, Kaj Blennow, Henrik Zetterberg, Jonas Eriksson, Mark Lubberink, Michael Schöll

    Measuring synaptic density in vivo using positron emission tomography (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clinical applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathology and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic density, the potential role of fluid-based biomarkers for SV2A, and related future perspectives.

    更新日期:2019-03-13
  • Cerebrospinal fluid biomarker for Parkinson's disease: An overview
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2018-12-10
    Fabian Maass, Isabel Schulz, Paul Lingor, Brit Mollenhauer, Mathias Bähr

    In Parkinson's disease (PD), there is a wide field of recent and ongoing search for useful biomarkers for early and differential diagnosis, disease monitoring or subtype characterization. Up to now, no biofluid biomarker has entered the daily clinical routine. Cerebrospinal fluid (CSF) is often used as a source for biomarker development in different neurological disorders because it reflects changes in central-nervous system homeostasis. This review article gives an overview about different biomarker approaches in PD, mainly focusing on CSF analyses. Current state and future perspectives regarding classical protein markers like alpha‑synuclein, but also different “omics” techniques are described. In conclusion, technical advancements in the field already yielded promising results, but further multicenter trials with well-defined cohorts, standardized protocols and integrated data analysis of different modalities are needed before successful translation into routine clinical application.

    更新日期:2019-03-13
  • Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2018-12-08
    Ann D. Cohen, Susan M. Landau, Beth E. Snitz, William E. Klunk, Kaj Blennow, Henrik Zetterberg

    Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). The development of fluid and PET biomarkers for Alzheimer's disease (AD), has allowed for detection of Aβ pathology in vivo and marks a major advancement in understanding the role of Aβ in Alzheimer's disease (AD). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms are used for staging of the disease. Therefore, sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research. Here, we discuss fluid and PET biomarkers for Aβ and their application.

    更新日期:2019-03-13
  • Biomarkers for tau pathology
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2018-12-07
    Michael Schöll, Anne Maass, Niklas Mattsson, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, William Jagust

    The aggregation of fibrils of hyperphosphorylated and C-terminally truncated microtubule-associated tau protein characterizes 80% of all dementia disorders, the most common neurodegenerative disorders. These so-called tauopathies are hitherto not curable and their diagnosis, especially at early disease stages, has traditionally proven difficult. A keystone in the diagnosis of tauopathies was the development of methods to assess levels of tau protein in vivo in cerebrospinal fluid, which has significantly improved our knowledge about these conditions. Tau proteins have also been measured in blood, but the importance of tau-related changes in blood is still unclear. The recent addition of positron emission tomography ligands to visualize, map and quantify tau pathology has further contributed with information about the temporal and spatial characteristics of tau accumulation in the living brain. Together, the measurement of tau with fluid biomarkers and positron emission tomography constitutes the basis for a highly active field of research. This review describes the current state of biomarkers for tau biomarkers derived from neuroimaging and from the analysis of bodily fluids and their roles in the detection, diagnosis and prognosis of tau-associated neurodegenerative disorders, as well as their associations with neuropathological findings, and aims to provide a perspective on how these biomarkers might be employed prospectively in research and clinical settings.

    更新日期:2019-03-13
  • Review: Fluid biomarkers in the human prion diseases
    Mol. Cell. Neurosci. (IF 2.855) Pub Date : 2018-12-04
    Andrew G.B. Thompson, Simon H. Mead

    The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. Blood has been a more challenging analyte, but has now also yielded valuable biomarkers. Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.

    更新日期:2019-03-13
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