Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial Abnormalities and Synaptic Damage in Huntington’s Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Huntington’s disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Availability of Data and Materials

Not applicable

Presented research is in compliance with ethical standards.

Abbreviations

ADRM1:

Adhesion regulating molecule 1

ATM:

Ataxia-telangiectasia mutated

BACHD:

Bacterial artificial chromosome Huntington’s disease

BDNF:

Brain-derived neurotrophic factor

BER:

Base excision repair

CBP:

CREB-binding protein

COX1:

Cytochrome oxidase complex 1

CtBP:

Transcriptional corepressor C-terminal-binding protein

CypD:

Cyclophilin D

DARPP-32:

Dopamine-regulated neuronal phosphoprotein

DRP1:

Dynamin-related protein 1

ER:

Endoplasmic reticulum

ESCs:

Embryonic stem cells,

ETC:

Electron transport chain

FEN1:

Flap endonuclease 1

Fis1:

Mitochondrial fission 1 protein

GABA:

gamma-aminobutyric acid

GluN1:

N-methyl D-aspartate receptor subtype 1

GRP75:

Glucose-related protein 75

H2O2 :

Hydrogen peroxide

HAP1:

Huntington’s associated protein 1

HD:

Huntington’s disease

Htt:

Huntingtin protein

IP3R3:

Inositol 1,4,5-trisphosphate receptor, type 3

iPSCs:

Induced pluripotent stem cells

MAP2:

Microtubule-associated protein 2

Mfn1:

Mitofusin 1

Mfn2:

Mitofusin 2

mHtt:

Mutant huntingtin

MPT:

Mitochondrial permeability transition pore

MSNs:

Medium spiny neurons

MtDNA:

Mitochondrial DNA

NAKAP:

Nuclear scaffold protein

NCOR:

Nuclear corepressor

NII:

Neuronal intranuclear inclusions

NMDAR:

N-methyl-D-aspartate receptor

NOX:

Nicotinamide adenine dinucleotide phosphate oxidase

NRF1:

Nuclear respiratory factor 1,

NRF2:

Nuclear respiratory factor 2

NRSF:

Neuron-restrictive silencer factor

NRSF:

Neuron-restrictive silencer factor

NSCs:

Neural stem cells

OH-:

Hydroxyl radical

OH8dG:

8‐hydroxy‐2‐deoxyguanosine

OPA1:

Optic atrophy protein 1

PGC-1a:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PINK1:

PTEN-induced kinase 1

PolyQ:

Polyglutamine expansion

PRC2:

Polycomb repressive complex 2

PSD95:

Postsynaptic density protein

RNA:

Reactive nitrogen species

ROS:

Reactive oxygen species

Tcerg1/CA150:

The transcription elongation regulator 1

TFAM:

Mitochondrial transcription factor A

Tomm 40:

Translocase of outer mitochondrial membrane 40 homolog

YAC:

Yeast artificial chromosome

References

  1. Huntington G (1872) On Chorea, Medical and Surgical Reporter.

  2. Bhattacharyya KB (2016) The story of George Huntington and his disease. Ann Indian Acad Neurol 19(1):25–28

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bates GP (2005) History of genetic disease: the molecular genetics of Huntington disease - a history. Nat Rev Genet 6(10):766–773

    Article  CAS  PubMed  Google Scholar 

  4. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA et al. (2015) Huntington disease. Nat Rev Dis Primers 1:15005

    Article  PubMed  Google Scholar 

  5. Okun MS, Thommi N (2004) Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Neurology. 63(2):340–343

    Article  PubMed  Google Scholar 

  6. Moscovich M, Munhoz RP, Becker N, Barbosa BR, Espay AJ, Weiser R, Teive HA (2011) Américo Negrette and Huntington’s disease. Arq Neuropsiquiatr 69(4):711–713

    Article  PubMed  Google Scholar 

  7. Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I et al. (1987) Homozygotes for Huntington’s disease. Nature. 326(6109):194–197

    Article  CAS  PubMed  Google Scholar 

  8. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G et al. (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci USA 101(10):3498–3503

  9. Wexler NS (2013) Three decades of caring for the Venezuelan Huntington’s disease families. Lancet Neurol 12(8):738

    Article  PubMed  Google Scholar 

  10. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K et al. (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306(5940):234–238

    Article  CAS  PubMed  Google Scholar 

  11. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983

  12. Wheeler VC, Persichetti F, McNeil SM, Mysore JS, Mysore SS, MacDonald ME, Myers RH, Gusella JF et al. (2007) US-Venezuela Collaborative Research Group, Factors associated with HD CAG repeat instability in Huntington disease. J Med Genet 44(11):695–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McColgan P, Tabrizi SJ (2018) Huntington’s disease: a clinical review. Eur J Neurol 25(1):24–34

    Article  CAS  PubMed  Google Scholar 

  14. Kirkwood SC, Su JL, Conneally P, Foroud T (2001) Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol 58(2):273–278

    Article  CAS  PubMed  Google Scholar 

  15. Montoya A, Price BH, Menear M, Lepage M (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31(1):21–29

    PubMed  PubMed Central  Google Scholar 

  16. Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98

    Article  CAS  PubMed  Google Scholar 

  17. Pla P, Orvoen S, Saudou F, David DJ, Humbert S (2014) Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms. Front Behav Neurosci 8:135

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577

    Article  CAS  PubMed  Google Scholar 

  19. Laforet GA, Sapp E, Chase K, McIntyre C, Boyce FM, Campbell M, Cadigan BA, Warzecki L et al. (2001) Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 21(23):9112–9123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27(9):1083–1091

    Article  PubMed  Google Scholar 

  21. Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO Jr, Miller G, Tagle DA (1998) Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 20(2):198–202

    Article  CAS  PubMed  Google Scholar 

  22. Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet 19(20):3919–3935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R, Phansalkar A, Strand A, Torcassi C et al. (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 3(5):e82

    Article  PubMed  PubMed Central  Google Scholar 

  24. Saudou F, Humbert S (2016) The biology of Huntingtin. Neuron 89(5):910–26

    Article  CAS  PubMed  Google Scholar 

  25. Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH (2012) Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum Mol Genet 21(2):406–420

    Article  CAS  PubMed  Google Scholar 

  26. Reddy PH, Mao P, Manczak M (2009) Mitochondrial structural and functional dynamics in Huntington’s disease. Brain Res Rev 61(1):33–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Reddy PH (1822) Shirendeb UP (2012) Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington’s disease. Biochim Biophys Acta 2:101–110

    Google Scholar 

  28. Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet 20(7):438–1455

    Article  Google Scholar 

  29. Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L (2011) PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 6(1):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, Tran DD, Vrieze BT, Legendre-Guillemin V et al. (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24(18):8195–8209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Smith-Dijak AI, Sepers MD, Raymond LA (2019) Alterations in synaptic function and plasticity in Huntington disease. J Neurochem 150(4):346–365

    Article  CAS  PubMed  Google Scholar 

  32. Acevedo-Torres K, Berríos L, Rosario N, Dufault V, Skatchkov S, Eaton MJ, Torres-Ramos CA, Ayala-Torres S (2009) Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington’s disease. DNA Repair (Amst.) 8(1):126–136

    Article  CAS  Google Scholar 

  33. Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121(2):493–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Golas MM (2018) Human cellular models of medium spiny neuron development and Huntington disease. Life Sci 209:179–196

    Article  CAS  PubMed  Google Scholar 

  36. Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL (2008) Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci USA 105(43):16707–16712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carter RL, Chan AW (2012) Pluripotent stem cells models for Huntington’s disease: prospects and challenges. J Genet Genomics 39(6):253–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kisby B, Jarrell JT, Agar ME, Cohen DS, Rosin ER, Cahill CM, Rogers JT, Huang X (2019) Alzheimer’s disease and its potential alternative therapeutics. J Alzheimer’s Dis Parkinsonism 9(5):477

    Google Scholar 

  39. Dennis CV, Suh LS, Rodriguez ML, Kril JJ, Sutherland GT (2016) Human adult neurogenesis across the ages: an immunohistochemical study. Neuropathol Appl Neurobiol 42(7):621–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kerkis I, Haddad MS, Valverde CW, Glosman S (2015) Neural and mesenchymal stem cells in animal models of Huntington’s disease: past experiences and future challenges. Stem Cell Res Ther 14(6):232

    Article  Google Scholar 

  41. Naphade S, Tshilenge KT, Ellerby LM (2019) Modeling polyglutamine expansion diseases with induced pluripotent stem cells. Neurotherapeutics 16(4):979–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S, Melov S, Ellerby LM (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11(2):253–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Geater C, Hernandez S, Thompson L, Mattis VB (2018) Cellular models: HD patient-derived pluripotent stem cells. Methods Mol Biol 1780:41–73

    Article  CAS  PubMed  Google Scholar 

  44. Mattis VB, Svendsen SN (2017) Modeling Huntington’s disease with patient-derived neurons. Brain Res 1656(2017):76–87

    Article  CAS  PubMed  Google Scholar 

  45. Singer E, Walter C, Weber JJ, Krahl A, Mau-Holzmann UA, Rischert N, Riess O, Clemensson LE et al. (2017) Reduced cell size, chromosomal aberration and altered proliferation rates are characteristics and confounding factors in the STHdh cell model of Huntington disease. Sci Rep 7:16880

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wheeler VC, White JK, Gutekunst C, Vrbanac V, Weaver M, Li X, Li S, Yi H et al. (2000) Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells. Hum Mol Genet 9(19):2799–2809

    Article  PubMed  Google Scholar 

  47. Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F, Cattaneo E, MacDonald ME (2000) Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells. Hum Mol Genet 9(19):2799–2809

    Article  CAS  PubMed  Google Scholar 

  48. Wanderer J, Morton AJ (2007) Differential morphology and composition of inclusions in the R6/2 mouse and PC12 cell models of Huntington’s disease. Histochem Cell Biol 127(5):473–484

    Article  CAS  PubMed  Google Scholar 

  49. Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ (2006) Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington’s disease by ubiquilin. Hum Mol Genet 15(6):1025–1041

    Article  CAS  PubMed  Google Scholar 

  50. Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, Clementi E, Hackam A et al. (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci 20(10):3705–3713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100(18):10483–10487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chaves G, Stanley J, Pourmand N (2019) Mutant huntingtin affects diabetes and Alzheimer’s markers in human and cell models of Huntington’s disease. Cells 8(9):962

    Article  CAS  PubMed Central  Google Scholar 

  53. L’Episcopo F, Drouin-Ouellet J, Tirolo C, Pulvirenti A, Giugno R, Testa N, Caniglia S, Serapide MF et al. (2016) GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington’s disease: involvement of astrocyte-neuron interactions. Cell Death Dis 7(4):e2206

    Article  PubMed  PubMed Central  Google Scholar 

  54. Valenza M, Marullo M, Di Paolo E, Cesana E, Zuccato C, Biella G, Cattaneo E (2015) Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease. Cell Death Differ 22(4):690–702

    Article  CAS  PubMed  Google Scholar 

  55. Hsiao H, Chen Y, Chen H, Tu P, Chern Y (2013) A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington’s disease. Hum Mol Genet 22(9):1826–1842

    Article  CAS  PubMed  Google Scholar 

  56. Bradford J, Shin JY, Roberts M, Wang CE, Li XJ, Li S (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci USA 106(52):22480–22485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Valencia A, Reeves PB, Sapp E, Li X, Alexander J, Kegel KB, Chase K, Aronin N et al. (2010) Mutant huntingtin and glycogen synthase kinase 3-beta accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington’s disease. J Neurosci Res 88(1):179–190

    Article  CAS  PubMed  Google Scholar 

  58. Chu-LaGraff Q, Kang X, Messer A (2001) Expression of the Huntington’s disease transgene in neural stem cell cultures from R6/2 transgenic mice. Brain Res Bull 56(34):307–312

    Article  CAS  PubMed  Google Scholar 

  59. Phillips W, Morton AJ, Barker AR (2005) Abnormalities of neurogenesis in the R6/2 mouse model of Huntington’s disease are attributable to the in vivo microenvironment. J Neurosci 25(50):11564–11576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Menalled LB, Chesselet MF (2002) Mouse models of Huntington’s disease. Trends Pharmacol Sci 23(1):32–39

    Article  CAS  PubMed  Google Scholar 

  61. Ehrnhoefer DE, Butland SL, Pouladi MA, Hayden MR (2009) Mouse models of Huntington disease: variations on a theme. Dis Model Mech 2(34):123–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet MF (2003) Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J Comp Neurol 465(1):11–26

    Article  CAS  PubMed  Google Scholar 

  63. Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel JP, Gusella GF, Joyner AL (1995) Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 269(5222):407–410

    Article  CAS  PubMed  Google Scholar 

  64. Nasir J, Floresco SB, O’Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD et al. (1995) Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81(5):811–823

    Article  CAS  PubMed  Google Scholar 

  65. Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 11(2):155–163

    Article  CAS  PubMed  Google Scholar 

  66. Menalled LB (2005) Knock-in mouse models of Huntington’s disease. NeuroRx. 2(3):465–470

    Article  PubMed  PubMed Central  Google Scholar 

  67. Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101(1):57–66

    Article  CAS  PubMed  Google Scholar 

  68. Crook ZR, Housman D (2011) Huntington’s disease: can mice lead the way to treatment? Neuron 69(3):423–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet MF (2004) Genetic mouse models of Huntington’s and Parkinson’s diseases: illuminating but imperfect. Trends Neurosci 27(11):691–697

    Article  CAS  PubMed  Google Scholar 

  70. Blum D, Herrera F, Francelle L, Mendes T, Basquin M, Obriot H, Demeyer D, Sergeant N et al. (2015) Mutant huntingtin alters Tau phosphorylation and subcellular distribution. Hum Mol Genet 24(1):76–85

    Article  CAS  PubMed  Google Scholar 

  71. Gratuze M, Noël A, Julien C, Cisbani G, Milot-Rousseau P, Morin F, Dickler M, Goupil C et al. (2015) Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington’s disease. Hum Mol Genet 24(1):86–99

    Article  CAS  PubMed  Google Scholar 

  72. L’Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Cossetti C, D’Adamo P, Zardini E et al. (2011) Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neurobiol Dis 41(2):508–527

    Article  PubMed  Google Scholar 

  73. Dvorzhak A, Semtner M, Faber DS, Grantyn R (2013) Tonic mGluR5/CB1-dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin. J Physiol 591(4):1145–1166

    Article  CAS  PubMed  Google Scholar 

  74. Rubinsztein DC (2002) Lessons from animal models of Huntington’s disease. Trends Genet 18(4):202–209

    Article  CAS  PubMed  Google Scholar 

  75. Cepeda C, Cummings DM, André VM, Holley SM, Levine MS (2010) Genetic mouse models of Huntington’s disease: focus on electrophysiological mechanisms. ASN Neuro. 2(2):e00033

    Article  PubMed  PubMed Central  Google Scholar 

  76. Li XJ, Li S (2015) Large animal models of Huntington’s disease. Curr Top Behav Neurosci 22:149–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yan S, Tu Z, Liu Z, Fan N, Yang H, Yang S, Yang W, Zhao Y, Ouyang Z et al. (2018) A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell 173(4):989–1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yan S, Li S, Li XJ (2019) Use of large animal models to investigate Huntington’s diseases. Cell Regen 8(1):9–11

    Article  PubMed  PubMed Central  Google Scholar 

  79. Howland D, Ellederova Z, Aronin N, Fernau D, Gallagher J, Taylor Hennebold J, Weiss AR, Gray-Edwards H et al. (2020) Large animal models of Huntington’s disease: what we have learned and where we need to go next. J Huntingtons Dis 9(3):201–216

    Article  PubMed  PubMed Central  Google Scholar 

  80. Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P (2011) Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev 67(1–2):103–118

    Article  CAS  PubMed  Google Scholar 

  81. Sawant N, Reddy PH (2019) Role of phosphorylated Tau and glucose synthase kinase 3 beta in Huntington’s disease progression. J Alzheimers Dis 72(s1):S177–S191

    Article  CAS  PubMed  Google Scholar 

  82. Pantiya P, Thonusin C, Chattipakorn N, Chattipakorn SC (2020) Mitochondrial abnormalities in neurodegenerative models and possible interventions: focus on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease. Mitochondrion 55:14–47

    Article  CAS  PubMed  Google Scholar 

  83. Li S, Li XJ (2006) Multiple pathways contribute to the pathogenesis of Huntington disease. Mol Neurodegener 1:19

    Article  PubMed  PubMed Central  Google Scholar 

  84. Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5(8):731–736

    Article  CAS  PubMed  Google Scholar 

  85. Reddy PH (2014) Increased mitochondrial fission and neuronal dysfunction in Huntington’s disease: implications for molecular inhibitors of excessive mitochondrial fission. Drug Discov Today 19(7):951–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Oliver D, Reddy PH (2019) Dynamics of dynamin-related protein 1 in Alzheimer’s disease and other neurodegenerative diseases. Cells 8(9):961

    Article  CAS  PubMed Central  Google Scholar 

  87. Manczak M, Reddy PH (2015) Mitochondrial division inhibitor 1 protects against mutant huntingtin-induced abnormal mitochondrial dynamics and neuronal damage in Huntington’s disease. Hum Mol Genet 24(25):7308–7325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Joshi AU, Ebert AE, Haileselassie B, Mochly-Rosen D (2019) Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington’s disease. J Mol Cell Cardiol 127:125–133

    Article  CAS  PubMed  Google Scholar 

  89. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA et al. (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17(3):377–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Haun F, Nakamura T, Shiu AD, Cho DH, Tsunemi T, Holland EA, La Spada AR, Lipton SA (2013) S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington’s disease Antioxid. Redox Signal 19(11):1173–1184

    Article  CAS  Google Scholar 

  91. Huang ZN, Chung HM, Fang SC, Her LS (2017) Adhesion regulating molecule 1 mediates HAP40 overexpression-induced mitochondrial defects. Int J Biol Sci 13(11):1420–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huang ZN, Her LS (2017) The ubiquitin receptor ADRM1 modulates HAP40-induced proteasome activity. Mol Neurobiol 54(9):7382–7400

    Article  CAS  PubMed  Google Scholar 

  93. Li X, Huang L, Lan J, Feng X, Li P, Wu L, Peng Y (2021) Molecular mechanisms of mitophagy and its roles in neurodegenerative diseases. Pharmacol Res 163:105240

    Article  CAS  PubMed  Google Scholar 

  94. Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, Reddy AP (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum Mol Genet 27(14):2502–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Manczak M, Kandimalla R, Yin X, Reddy PH (2019) Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity. Hum Mol Genet 28(2):177–199

    Article  CAS  PubMed  Google Scholar 

  96. Jamwal S, Blackburn JK, Elsworth JD (2020) PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders. Pharmacol Ther 219(2020):107705

    PubMed  PubMed Central  Google Scholar 

  97. Johnson J, Mercado-Ayon E, Mercado-Ayon Y, Dong YN, Halawani S, Ngaba L, Lynch DR (2020) Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch Biochem Biophys 702:108698

    Article  PubMed  Google Scholar 

  98. Kang TC (2020) Nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitochondrial dynamics/mitophagy in neurological diseases. Antioxidants (Basel, Switzerland) 9(7):617

    CAS  Google Scholar 

  99. Siddiqui A, Rivera-Sánchez S, Castro Mdel R, Acevedo-Torres K, Rane A, Torres-Ramos CA, Nicholls DG, Andersen JK et al. (2012) Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington’s disease. Free Radic Biol Med 53(7):1478–1488

    Article  CAS  PubMed  Google Scholar 

  100. Guo Q, Huang B, Cheng J, Seefelder M, Engler T, Pfeifer G, Oeckl P, Otto M, Moser F et al. (2018) The cryo-electron microscopy structure of huntingtin. Nature 555(7694):117–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ratovitski T, Chighladze E, Arbez N, Boronina T, Herbrich S, Cole RN, Ross CA (2012) Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle. 11(10):2006–2021

    Article  PubMed  PubMed Central  Google Scholar 

  102. Senatorov VV, Charles V, Reddy PH, Tagle DA, Chuang DM (2003) Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington’s disease. Mol Cell Neurosci 22(3):285–297

    Article  CAS  PubMed  Google Scholar 

  103. Li SH, Li XJ (2004) Huntingtin–protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 20(3):146–154

    Article  PubMed  Google Scholar 

  104. Strehlow ANT, Li JZ, Myers RM (2007) Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. Hum Mol Genet 16(4):391–409

    Article  CAS  PubMed  Google Scholar 

  105. Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM, Truant R (2007) Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet 16(21):2600–2615

    Article  CAS  PubMed  Google Scholar 

  106. Benn CL, Landles C, Li H, Strand AD, Woodman B, Sathasivam K, Li SH, Ghazi-Noori S et al. (2005) Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington’s disease. Hum Mol Genet 14(20):3065–3078

    Article  CAS  PubMed  Google Scholar 

  107. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277(5334):1990–1993

    Article  CAS  PubMed  Google Scholar 

  108. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE et al. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90(3):537–548

    Article  CAS  PubMed  Google Scholar 

  109. Kim M, Lee HS, LaForet G, McIntyre C, Martin EJ, Chang P, Kim TW, Williams M et al. (1999) Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci 19(3):964–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vitet H, Brandt V, Saudou F (2020) Traffic signaling: new functions of huntingtin and axonal transport in neurological disease. Curr Opin Neurobiol 63:122–130

    Article  CAS  PubMed  Google Scholar 

  111. Pal A, Severin F, Lommer B, Shevchenko A, Zerial M (2006) Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington’s disease. J Cell Biol 172(4):605–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu LL, Zhou XF (2009) Huntingtin associated protein 1 and its functions. Cell Adh Migr 3(1):71–76

    Article  PubMed  PubMed Central  Google Scholar 

  113. Wilbur JD, Chen CY, Manalo V, Hwang PK, Fletterick RJ, Brodsky FM (2008) Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (Hip1-related protein) is regulated by clathrin light chain. J Biol Chem 283(47):32870–32879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fan MM, Raymond LA (2007) N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 81(5–6):272–293

    Article  CAS  PubMed  Google Scholar 

  115. Elias S, Thion MS, Yu H, Sousa CM, Lasgi C, Morin X, Humbert S (2014) Huntingtin regulates mammary stem cell division and differentiation. Stem Cell Reports 2(4):491–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Godin JD, Colombo K, Molina-Calavita M, Keryer G, Charrin BC, Dietrich P, Volvert ML, Guillemot F et al. (2010) Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 67(3):392–406

    Article  CAS  PubMed  Google Scholar 

  117. Atwal RS, Truant R (2008) A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy. Autophagy 4(1):91–93

    Article  PubMed  Google Scholar 

  118. Cherubini M, Lopez-Molina L, Gines S (2020) Mitochondrial fission in Huntington’s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and reactive oxygen species (ROS) homeostasis. Neurobiol Dis 136:104741

    Article  CAS  PubMed  Google Scholar 

  119. Valor LM (2015) Transcription, epigenetics and ameliorative strategies in Huntington’s Disease: a genome-wide perspective. Mol Neurobiol 51(1):406–423

    Article  CAS  PubMed  Google Scholar 

  120. Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Radic Biol Med 63:1–29

    Article  CAS  PubMed  Google Scholar 

  121. Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD et al. (1996) Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J Biol Chem 271(32):19385–19394

    Article  CAS  PubMed  Google Scholar 

  122. Reddy PH, Williams M, Tagle DA (1999) Recent advances in understanding the pathogenesis of Huntington’s disease. Trends Neurosci 22(6):248–255

    Article  CAS  PubMed  Google Scholar 

  123. Sorolla MA, Rodríguez-Colman MJ, Vall-llaura N, Tamarit J, Ros J, Cabiscol E (2012) Protein oxidation in Huntington disease. Biofactors 38(3):173–185

    Article  CAS  PubMed  Google Scholar 

  124. Kazantsev A, Preisinger E, Dranovsky A, Goldgaber D, Housman D (1999) Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci USA 96(20):11404–11409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP et al. (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 97(12):6763–6768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH et al. (2005) p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 47(1):29–41

    Article  CAS  PubMed  Google Scholar 

  127. Illuzzi JL, Vickers CA, Kmiec EB (2011) Modifications of p53 and the DNA damage response in cells expressing mutant form of the protein huntingtin. J Mol Neurosci 45(2):256–268

    Article  CAS  PubMed  Google Scholar 

  128. Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR et al. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35(1):76–83

    Article  CAS  PubMed  Google Scholar 

  129. Bithell A, Johnson R, Buckley NJ (2009) Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington’s disease. Biochem Soc Trans 37(Pt 6):1270–1275

    Article  CAS  PubMed  Google Scholar 

  130. Benn CL, Sun T, Sadri-Vakili G, McFarland KN, DiRocco DP, Yohrling GJ, Clark TW, Bouzou B et al. (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci 28(42):10720–10733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zheng Z, Diamond MI (2012) Huntington disease and the huntingtin protein. Prog Mol Biol Transl Sci 107:189–214

    Article  CAS  PubMed  Google Scholar 

  132. Valor LM, Guiretti D (2014) What’s wrong with epigenetics in Huntington’s disease? Neuropharmacology 80:103–114

    Article  CAS  PubMed  Google Scholar 

  133. Vashishtha M, Ng CW, Yildirim F, Gipson TA, Kratter IH, Bodai L, Song W, Lau A et al. (2013) Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci USA 110(32):E3027–E3036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier KA, Smith KM, Ferrante RJ (2006) ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington’s disease. Proc Natl Acad Sci USA 103(50):19176–19181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Seong IS, Woda JM, Song JJ, Lloret A, Abeyrathne PD, Woo CJ, Gregory G, Lee JM et al. (2010) Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet 19(4):573–583

    Article  CAS  PubMed  Google Scholar 

  136. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59–69

    Article  CAS  PubMed  Google Scholar 

  137. Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M et al. (2009) Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 18(16):3048–3065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Millecamps S, Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14(3):161–176

    Article  CAS  PubMed  Google Scholar 

  139. Chang DT, Rintoul GL, Pandipati S, Reynolds IL (2006) Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis 22(2):388–400

    Article  CAS  PubMed  Google Scholar 

  140. Illarioshkin SN, Klyushnikov SA, Vigont VA, Seliverstov YA, Kaznacheyeva EV (2018) Molecular pathogenesis in Huntington’s disease. Biochemistry (Mosc.) 83(9):1030–1039

    Article  CAS  Google Scholar 

  141. Zhao X, Chen XQ, Han E, Hu Y, Paik P, Ding Z, Overman J, Lau AL et al. (2016) TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease. Proc Natl Acad Sci USA 113(38):E5655–E5664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Li H, Wyman T, Yu ZX, Li SH, Li XJ (2003) Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release. Hum Mol Genet 12(16):2021–2030

    Article  CAS  PubMed  Google Scholar 

  143. Rozas JL, Gómez-Sánchez L, Tomás-Zapico C, Lucas JJ, Fernández-Chacón R (2010) Presynaptic dysfunction in Huntington’s disease. Biochem Soc Trans 38(2):488–492

    Article  CAS  PubMed  Google Scholar 

  144. Ginés S, Bosch M, Marco S, Gavaldà N, Díaz-Hernández M, Lucas JJ, Canals JM, Alberch J (2006) Reduced expression of the TrkB receptor in Huntington’s disease mouse models and in human brain. Eur J Neurosci 23(3):649–658

    Article  PubMed  Google Scholar 

  145. Chao MV, Hempstead BL (1995) p75 and Trk: a two-receptor system. Trends Neurosci 18(7):321–326

    Article  CAS  PubMed  Google Scholar 

  146. Liot G, Zala D, Pla P, Mottet G, Piel M, Saudou F (2013) Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J Neurosci 33(15):6298–6309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Plotkin JL, Surmeier DJ (2015) Corticostriatal synaptic adaptations in Huntington’s disease. Curr Opin Neurobiol 33:53–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Murmu RP, Li W, Szepesi Z, Li JY (2015) Altered sensory experience exacerbates stable dendritic spine and synapse loss in a mouse model of Huntington’s disease. J Neurosci 35(1):287–298

    Article  PubMed  PubMed Central  Google Scholar 

  149. Plotkin JL, Day M, Peterson JD, Xie Z, Kress GJ, Rafalovich I, Kondapalli J, Gertler TS, Flajolet M et al.(2014) Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease. Neuron 83(1):178–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Koch ET, Raymond LA (2019) Dysfunctional striatal dopamine signaling in Huntington’s disease. J Neurosci Res 97(12):1636–1654

    CAS  PubMed  Google Scholar 

  151. Reiner A, Deng YP (2018) Disrupted striatal neuron inputs and outputs in Huntington’s disease. CNS Neurosci Ther 24(4):250–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Spokes EG (1980) Neurochemical alterations in Huntington’s chorea: a study of post-mortem brain tissue. Brain 103(1):179–210

    Article  CAS  PubMed  Google Scholar 

  153. Garrett MC, Soares-da-Silva P (1992) Increased cerebrospinal fluid dopamine and 3,4-dihydroxyphenylacetic acid levels in Huntington’s disease: evidence for an overactive dopaminergic brain transmission. J Neurochem 58(1):101–106

    Article  CAS  PubMed  Google Scholar 

  154. Sun Y, Savanenin A, Reddy PH, Liu YF (2001) Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95. J Biol Chem 276(27):24713–24718

    Article  CAS  PubMed  Google Scholar 

  155. Milnerwood AJ, Kaufman AM, Sepers MD, Gladding CM, Zhang L, Wang L, Fan J, Coquinco A et al. (2012) Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington’s disease mice. Neurobiol Dis 48(1):40–51

    Article  CAS  PubMed  Google Scholar 

  156. Rosas-Arellano A, Estrada-Mondragón A, Mantellero CA, Tejeda-Guzmán C, Castro MA (2018) The adjustment of γ-aminobutyric acid A tonic subunits in Huntington’s disease: from transcription to translation to synaptic levels into the neostriatum. Neural Regen Res 13(4):584–590

    Article  PubMed  PubMed Central  Google Scholar 

  157. Wang EA, Cepeda C, Levine MS (2012) Cognitive deficits in Huntington’s disease: Insights from animal models. Curr Tran Geriatr Gerontol Rep 1:29–38

    Article  CAS  Google Scholar 

  158. Bao J, Sharp AH, Wagster MV, Becher M, Schilling G, Ross CA, Dawson VL, Dawson TM (1996) Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin. Proc Natl Acad Sci USA 93(10):5037–5042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Rasola A, Sciacovelli M, Pantic B, Bernardi P (2010) Signal transduction to the permeability transition pore. FEBS Lett 584(10):1989–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283(9):5780–5789

    Article  CAS  PubMed  Google Scholar 

  161. Quintanilla RA, Jin YN, von Bernhardi R, Johnson GV (2013) Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol Neurodegener 8:45

    Article  PubMed  PubMed Central  Google Scholar 

  162. Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281(46):34785–34795

    Article  CAS  PubMed  Google Scholar 

  163. Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS et al. (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16(1):61–77

    Article  CAS  PubMed  Google Scholar 

  164. Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39(2):227–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mackay JP, Nassrallah WB, Raymond LA (2018) Cause or compensation?-Altered neuronal Ca2+ handling in Huntington’s disease. CNS Neurosci Ther 24(4):301–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fernandes HB, Baimbridge KG, Church J, Hayden MR, Raymond LA (2007) Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington’s disease. J Neurosci 27(50):13614–13623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Oliveira JM, Chen S, Almeida S, Riley R, Gonçalves J, Oliveira CR, Hayden MR, Nicholls DG et al. (2006) Mitochondrial-dependent Ca2+ handling in Huntington’s disease striatal cells: effect of histone deacetylase inhibitors. J Neurosci 26(43):11174–11186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zeron MM, Fernandes HB, Krebs C, Shehadeh J, Wellington CL, Leavitt BR, Baimbridge KG, Hayden MR et al. (2004) Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington’s disease. Mol Cell Neurosci 25(3):469–479

    Article  CAS  PubMed  Google Scholar 

  169. Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M (2004) Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 13(14):1407–1420

    Article  CAS  PubMed  Google Scholar 

  170. Giacomello M, Hudec R, Lopreiato R (2011) Huntington’s disease, calcium, and mitochondria. Biofactors 37(3):206–218

    Article  CAS  PubMed  Google Scholar 

  171. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400

    Article  CAS  PubMed  Google Scholar 

  172. Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova B, Kaniakova M, Lichnerova K, Cerny J et al. (2014) Structure, function, and pharmacology of NMDA receptor channels. Physiol Res 63(Suppl 1):S191–S203

    Article  CAS  PubMed  Google Scholar 

  173. Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 5(2):160–170

    Article  CAS  PubMed  Google Scholar 

  174. Chen HS, Lipton SA (2006) The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97(6):1611–1626

    Article  CAS  PubMed  Google Scholar 

  175. Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA (2002) Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 33(6):849–860

    Article  CAS  PubMed  Google Scholar 

  176. Gladding CM, Raymond LA (2011) Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci 48(4):308–320

    Article  CAS  PubMed  Google Scholar 

  177. Parsons MP, Raymond LA (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorder. Neuron 82(2):279–293

    Article  CAS  PubMed  Google Scholar 

  178. Subramaniam S, Sixt KM, Barrow R, Snyder SH (2009) Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324(5932):1327–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Shipton OA, Paulsen O (2013) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B Biol Sci 369(1633):20130163

    Article  PubMed  Google Scholar 

  180. Cepeda C, Ariano MA, Calvert CR, Flores-Hernández J, Chandler SH, Leavitt BR, Hayden MR, Levine MS (2001) NMDA receptor function in mouse models of Huntington disease. J Neurosci Res 66(4):525–539

    Article  CAS  PubMed  Google Scholar 

  181. Marco S, Giralt A, Petrovic MM, Pouladi MA, Martínez-Turrilla R, Martínez-Hernández J, Kaltenbach LS, Torres-Peraza J et al. (2013) Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington’s disease models. Nat Med 19(8):1030–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Huang K, Yanai A, Kang R, Arstikaitis P, Singaraja RR, Metzler M, Mullard A, Haigh B et al. (2004) Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 44(6):977–986

    Article  CAS  PubMed  Google Scholar 

  183. Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A et al. (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15(12):1407–1413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Puddifoot C, Martel MA, Soriano FX, Camacho A, Vidal-Puig A, Wyllie DJ, Hardingham HE (2012) PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity. J Neurosci 32(20):6995–7000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinás R, Kristal BS, Hayden MR et al. (2005) Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci USA 102(7):2602–2607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Klapstein GJ, Fisher FS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS (2001) Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington’s disease transgenic mice. J Neurophysiol 86(6):2667–2677

    Article  CAS  PubMed  Google Scholar 

  187. Raymond LA (2017) Striatal synaptic dysfunction and altered calcium regulation in Huntington disease. Biochem Biophys Res Commun 483(4):1051–1062

    Article  CAS  PubMed  Google Scholar 

  188. Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante FJ, Beal MF (2001) Increased oxidative damage to DNA in a transgenic mouse model of Huntington’s disease. J Neurochem 79(6):1246–1249

    Article  CAS  PubMed  Google Scholar 

  189. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41(5):646–653

    Article  CAS  PubMed  Google Scholar 

  190. Askeland G, Dosoudilova Z, Rodinova M, Klempir J, Liskova I, Kuśnierczyk A, Bjørås M, Nesse G et al. (2018) Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients. Sci Rep 8(1):9817

    Article  PubMed  PubMed Central  Google Scholar 

  191. Stack EC, Matson WR, Ferrante RJ (2008) Evidence of oxidant damage in Huntington’s disease: translational strategies using antioxidants. Ann NY Acad Sci 1147:79–92

    Article  CAS  PubMed  Google Scholar 

  192. Túnez I, Sánchez-López F, Agüera E, Fernández-Bolaños R, Sánchez FM, Tasset-Cuevas I (2011) Important role of oxidative stress biomarkers in Huntington’s disease. J Med Chem 54(15):5602–5606

    Article  PubMed  Google Scholar 

  193. Long JD, Matson WR, Juhl AR, Leavitt BR, Paulsen JS (2012) PREDICT-HD Investigators and Coordinators of the Huntington Study Group 8OHdG as a marker for Huntington disease progression. Neurobiol Dis 46(3):625–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Strand JM, Scheffler K, Bjørås M, Eide L (2014) The distribution of DNA damage is defined by region-specific susceptibility to DNA damage formation rather than repair differences. DNA Repair (Amst) 18:44–51

    Article  CAS  Google Scholar 

  195. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C et al. (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 66(2):250–252

    Article  CAS  PubMed  Google Scholar 

  196. Ayala-Peña S (2013) Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic Biol Med 62:102–110

    Article  PubMed  PubMed Central  Google Scholar 

  197. Spiro C, McMurray CT (2003) Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability. Mol Cell Biol 23(17):6063–6074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447(7143):447–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Goula AV, Berquist BR, Wilson DM 3rd, Wheeler VC, Trottier Y, Merienne K (2009) Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington’s disease transgenic mice. PLoS Genet 5(12):1000749

    Article  Google Scholar 

  200. Manley K, Shirley TL, Flaherty L, Messer A (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23(4):471–473

    Article  CAS  PubMed  Google Scholar 

  201. Kovtun IV, McMurray CT (2001) Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet 27(4):407–411

    Article  CAS  PubMed  Google Scholar 

  202. Dragileva E, Hendricks A, Teed A, Gillis T, Lopez ET, Friedberg EC, Kucherlapati R, Edelmann W et al. (2009) Intergenerational and striatal CAG repeat instability in Huntington’s disease knock-in mice involve different DNA repair genes. Neurobiol Dis 33(1):37–47

    Article  CAS  PubMed  Google Scholar 

  203. Enokido Y, Tamura T, Ito H, Arumughan A, Komuro A, Shiwaku H, Sone M, Foulle R et al. (2010) Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol 189(3):425–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Maiuri T, Bowie LE, Truant R (2019) DNA repair signaling of Huntingtin: the next link between late-onset neurodegenerative disease and oxidative DNA damage. DNA Cell Biol 38(1):1–6

    Article  CAS  PubMed  Google Scholar 

  205. Morgan-Hughes JA, Hanna MG (1999) Mitochondrial encephalomyopathies: the enigma of genotype versus phenotype. Biochim Biophys Acta 1410(2):125–145

    Article  CAS  PubMed  Google Scholar 

  206. Trushina E, McMurray CT (2007) Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145(4):1233–1248

    Article  CAS  PubMed  Google Scholar 

  207. Grünewald T, Beal MF (1999) Bioenergetics in Huntington’s disease. Ann NY Acad Sci 893:203–213

    Article  PubMed  Google Scholar 

  208. Banoei MM, Houshmand M, Panahi MS, Shariati P, Rostami M, Manshadi MD, Majidizadeh T (2007) Huntington’s disease and mitochondrial DNA deletions: event or regular mechanism for mutant huntingtin protein and CAG repeats expansion?! Cell Mol Neurobiol 27(7):867–875

    Article  CAS  PubMed  Google Scholar 

  209. Horton TM, Graham BH, Corral-Debrinski M, Shoffner JM, Kaufman AE, Beal MF, Wallace DC (1995) Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington’s disease patients. Neurology 45(10):1879–1883

    Article  CAS  PubMed  Google Scholar 

  210. Yang JL, Weissman L, Bohr VA, Mattson MP (2008) Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 7(7):1110–1120

    Article  CAS  Google Scholar 

  211. Polidori MC, Mecocci P, Browne SE, Senin U, Beal MF (1999) Oxidative damage to mitochondrial DNA in Huntington’s disease parietal cortex. Neurosci Lett 272(1):53–56

    Article  CAS  PubMed  Google Scholar 

  212. Vercruysse P, Vieau D, Blum D, Petersén A, Dupuis L (2018) Hypothalamic alterations in neurodegenerative diseases and their relation to abnormal energy metabolism. Front Mol Neurosci 11:2

    Article  PubMed  PubMed Central  Google Scholar 

  213. Tsunemi T, La Spada AR (2012) PGC-1α at the intersection of bioenergetics regulation and neuron function: from Huntington’s disease to Parkinson’s disease and beyond. Prog Neurobiol 97(2):142–151

    Article  CAS  PubMed  Google Scholar 

  214. van der Burg JMM, Gardiner SL, Ludolph AC, Landwehrmeyer GB, Roos RAC, Aziz NA (2017) Body weight is a robust predictor of clinical progression in Huntington disease. Ann Neurol 82(3):479–483

    Article  PubMed  Google Scholar 

  215. Müller HP, Huppertz HJ, Dreyhaupt J, Ludolph AC, Tabrizi SJ, Roos RAC, Durr A, Landwehrmeyer GB et al. (2019) Combined cerebral atrophy score in Huntington’s disease based on atlas-based MRI volumetry: sample size calculations for clinical trials. Parkinsonism Relat Disord 63:179–184

    Article  PubMed  Google Scholar 

  216. Powers WJ, Videen TO, Markham J, McGee-Minnich L, Antenor-Dorsey JV, Hershey T, Perlmutter JS (2007) Selective defect of in vivo glycolysis in early Huntington’s disease striatum. Proc Natl Acad Sci USA 104(8):2945–2949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Duan W, Jiang M, Jin J (2014) Metabolism in HD: still a relevant mechanism? Mov Disord 29(11):1366–1374

    Article  PubMed  PubMed Central  Google Scholar 

  218. Süssmuth SD, Müller VM, Geitner C, Landwehrmeyer GB, Iff S, Gemperli A, Orth M (2015) Fat-free mass and its predictors in Huntington’s disease. J Neurol 262(6):1533–40

    Article  PubMed  Google Scholar 

  219. Popovic V, Svetel M, Djurovic M, Petrovic S, Doknic M, Pekic S, Miljic D, Milic N et al. (2004) Circulating and cerebrospinal fluid ghrelin and leptin: potential role in altered body weight in Huntington’s disease. Eur J Endocrinol 151(4):451–455

    Article  CAS  PubMed  Google Scholar 

  220. Lalić NM, Marić J, Svetel M, Jotić A, Stefanova E, Lalić K, Dragasević N, Milicić T et al. (2008) Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol 65(4):476–480

    Article  PubMed  Google Scholar 

  221. Labbadia J, Morimoto RI (2013) Huntington’s disease: underlying molecular mechanisms and emerging concepts. Trends Biochem Sci 38(8):378–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM at al. (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14(19):2871–2880

    Article  CAS  PubMed  Google Scholar 

  223. Solans A, Zambrano A, Rodríguez M, Barrientos A (2006) Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet 15(20):3063–3081

    Article  CAS  PubMed  Google Scholar 

  224. Damiano M, Galvan L, Déglon N (1802) Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1:52–61

    Google Scholar 

  225. Ismailoglu I, Chen Q, Popowski M, Yang L, Gross SS, Brivanlou AH (2014) Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol 391(2):230–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Franco-Iborra S, Vila M, Perier C (2018) Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson’s disease and Huntington’s disease. Front Neurosci 12:342

    Article  PubMed  PubMed Central  Google Scholar 

  227. Santamaría A, Pérez-Severiano F, Rodríguez-Martínez E, Maldonado PD, Pedraza Chaverri J, Ríos C, Segovia J (2001) Comparative analysis of superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington’s disease. Neurochem Res 26(4):419–424

    Article  PubMed  Google Scholar 

  228. Paul BD, Snyder SH (2019) Impaired redox signaling in Huntington’s disease: therapeutic implications. Front Mol Neurosci 12:68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Sbodio JI, Snyder SH, Paul BD (2019) Regulators of the transsulfuration pathway. Br J Pharmacol 176(4):583–593

    Article  CAS  PubMed  Google Scholar 

  230. Acuña AI, Esparza M, Kramm C, Beltrán FA, Parra AV, Cepeda C, Toro CA, Vidal RL et al. (2013) A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice. Nat Commun 4:2917

    Article  PubMed  Google Scholar 

  231. Berggren KL, Chen J, Fox J, Miller J, Dodds L, Dugas B, Vargas L, Lothian A et al. (2015) Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington’s disease. Redox Biol 4:363–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Franco-Iborra S, Plaza-Zabala A, Montpeyo M, Sebastian D, Vila M, Martinez-Vicente M (2021) Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy 17(3):672–689

    Article  CAS  PubMed  Google Scholar 

  233. Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J, Huh Y (2019) Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res 14(5):749–756

    Article  PubMed  PubMed Central  Google Scholar 

  234. Khalil B, El Fissi N, Aouane A, Cabirol-Pol MJ, Rival T, Liévens JC (2015) PINK1-induced mitophagy promotes neuroprotection in Huntington’s disease. Cell Death Dis. 6(1):e1617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Baldo B, Soylu R, Petersén A (2013) Maintenance of basal levels of autophagy in Huntington’s disease mouse models displaying metabolic dysfunction. PloS One 8(12):e83050

    Article  PubMed  PubMed Central  Google Scholar 

  236. Rodolfo C, Campello S, Cecconi F (2018) Mitophagy in neurodegenerative diseases. Neurochem Int 117:156–166

    Article  CAS  PubMed  Google Scholar 

  237. Wong YC, Holzbaur EL (2014) The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci 34(4):1293–1305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R, Arias E et al. (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 13(5):567–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Quinn P, Moreira PI, Ambrósio AF, Alves CH (2020) PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta Neuropathol Commun 8(1):189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Guedes-Dias P, de Proença J, Soares TR, Leitão-Rocha A, Pinho BR, Duchen MR (1852) Oliveira JM (2015) HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons. Biochim Biophys Acta 11:2484–2493

    Google Scholar 

  241. Guedes-Dias P (1832) Oliveira JM (2013) Lysine deacetylases and mitochondrial dynamics in neurodegeneration. Biochim Biophys Acta 8:1345–1359

    Google Scholar 

  242. Stavoe A, Holzbaur E (2019) Axonal autophagy: mini-review for autophagy in the CNS. Neurosci Lett 697:17–23

    Article  CAS  PubMed  Google Scholar 

  243. Rui YN, Xu Z, Patel B, Cuervo AM, Zhang S (2015) HTT/Huntingtin in selective autophagy and Huntington disease: a foe or a friend within? Autophagy 11(5):858–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Kiriyama Y, Nochi H (2015) The function of autophagy in neurodegenerative diseases. Int J Mol Sci 16(11):26797–26812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Wang XL, Feng ST, Wang ZZ, Chen NH, Zhang Y (2021) Role of mitophagy in mitochondrial quality control: mechanisms and potential implications for neurodegenerative diseases. Pharmacol Res 165:105433

    Article  CAS  PubMed  Google Scholar 

  246. Guo X, Sun X, Hu D, Wang YJ, Fujioka H, Vyas R, Chakrapani S, Joshi AU et al. (2016) VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington’s disease. Nat Commun 7:12646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Hwang S, Disatnik MH, Mochly-Rosen D (2015) Impaired GAPDH-induced mitophagy contributes to the pathology of Huntington’s disease. EMBO Mol Med 7(10):1307–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Shirasaki DI, Greiner ER, Al-Ramahi I, Gray M, Boontheung P, Geschwind DH, Botas J, Coppola G et al. (2012) Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75(1):41–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Fujita K, Nakamura Y, Oka T, Ito H, Tamura T, Tagawa K, Sasabe T, Katsuta A et al. (2013) A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases. Nat Commun 4:1816

    Article  PubMed  Google Scholar 

  250. Mani S, Swargiary G, Chadha R (2021) Mitophagy impairment in neurodegenerative diseases: pathogenesis and therapeutic interventions. Mitochondrion 57:270–293

    Article  CAS  PubMed  Google Scholar 

  251. Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA et al. (2012) PGC-1α rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 4(142):142ra97

    Article  PubMed  PubMed Central  Google Scholar 

  252. Johri A, Chandra A, Beal MF (2013) PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radic Biol Med 62:37–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Siddiqui A, Bhaumik D, Chinta SJ, Rane A, Rajagopalan S, Lieu CA, Lithgow GJ, Andersen JK (2015) Mitochondrial quality control via the PGC1α-TFEB signaling pathway is compromised by parkin Q311X mutation but independently restored by rapamycin. J Neurosci 35(37):12833–12844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Metzger S, Walter C, Riess O, Roos RA, Nielsen JE, Craufurd D (2013) REGISTRY Investigators of the European Huntington’s Disease Network, H.P. Nguyen, The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLoS One 8(7):e68951

  255. Swarnkar S, Chen Y, Pryor WM, Shahani N, Page DT, Subramaniam S (2015) Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington’s disease. Neurobiol Dis 82:66–77

    Article  CAS  PubMed  Google Scholar 

  256. Vidoni C, Secomandi E, Castiglioni A, Melone MAB, Isidoro C (2018) Resveratrol protects neuronal-like cells expressing mutant Huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation. Neurochem Int 117:174–187

    Article  CAS  PubMed  Google Scholar 

  257. Schwab LC, Garas SN, Drouin-Ouellet J, Mason SL, Stott SR, Barker RA (2015) Dopamine and Huntington’s disease. Expert Rev Neurother 15(4):445–458

    Article  CAS  PubMed  Google Scholar 

  258. Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL et al. (2014) Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci USA 111(47):16889–16894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, Vonsattel AP, Aronin N et al. (1997) Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 42(4):604–612

    Article  CAS  PubMed  Google Scholar 

  260. Kegel KB, Kim M, Sapp E, McIntyre C, Castaño JG, Aronin N, DiFiglia M (2000) Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 20(19):7268–7278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT et al. (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14(2):193–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Ruiz A, Alberdi E, Matute C (2018) Mitochondrial division inhibitor 1 (mdivi-1) protects neurons against excitotoxicity through the modulation of mitochondrial function and intracellular Ca2+ signaling. Front Mol Neurosci 17(11):3

    Article  Google Scholar 

  263. Solesio ME, Saez-Atienzar S, Jordan J, Galindo MF (2013) 3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway. Br J Pharmacol 168(1):63–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Fan LF, He PY, Peng YC, Du QH, Ma JY, Jin JX, Xu HZ, Li JR et al.(2017) Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis. Free Radic Biol Med 112:336–349

    Article  CAS  PubMed  Google Scholar 

  265. Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A et al. (2017) The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell 40(6):583–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10(6):839–850

    Article  CAS  PubMed  Google Scholar 

  267. Chen Y, Xu S, Wang N, Ma Q, Peng P, Yu Y, Zhang L, Ying Z et al. (2019) Dynasore suppresses mTORC1 activity and induces autophagy to regulate the clearance of protein aggregates in neurodegenerative diseases. Neurotox Res 36(1):108–116

    Article  CAS  PubMed  Google Scholar 

  268. Qi X, Qvit N, Su YC, Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126(Pt 3):789–802

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D, Qi X (2013) Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. J Clin Invest 123(12):5371–5388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Wright DJ, Renoir T, Smith ZM, Frazier AE, Francis PS, Thorburn DR, McGee SL, Hannan AJ et al.(2015) N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington’s disease. Transl Psychiatry 5(1):e492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Paul BD, Snyder SH (2019) Therapeutic applications of cysteamine and cystamine in neurodegenerative and neuropsychiatric diseases. Front Neurol 10:1315

    Article  PubMed  PubMed Central  Google Scholar 

  272. Rudenko O, Springer C, Skov LJ, Madsen AN, Hasholt L, Nørremølle A, Holst B (2019) Ghrelin-mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington’s disease. J Neuroendocrinol 31(7):e12699

    Article  PubMed  Google Scholar 

  273. Liu CS, Cheng WL, Kuo SJ, Li JY, Soong BW, Wei YH (2008) Depletion of mitochondrial DNA in leukocytes of patients with poly-Q diseases. J Neurol Sci 264(1–2):18–21

    Article  CAS  PubMed  Google Scholar 

  274. Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE, Alami NH, Wang B, Joshi A et al. (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78(1):65–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The research presented in this article was supported by NIH grants AG042178, AG047812, NS105473, AG060767, AG069333, and AG066347 (to PHR) and Alzheimer’s Association through a SAGA grant, Garrison Family Foundation Grant, and NIH grant AG063162 (to APR).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    Neha Sawant, Hallie Morton, Sudhir Kshirsagar & P. Hemachandra Reddy

  2. Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX, USA

    Arubala P. Reddy

  3. Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  4. Neurology, Department of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  5. Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  6. Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA

    P. Hemachandra Reddy

  7. Department of Internal Medicine, Cell Biology & Biochemistry, Public Health and School of Health Professions, Texas Tech University Health Sciences Center, Neuroscience & Pharmacology3601 4th Street, NeurologyLubbock, TX, 79430, USA

    P. Hemachandra Reddy

Authors
  1. Neha Sawant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hallie Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sudhir Kshirsagar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arubala P. Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Hemachandra Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.S., A.P.R and P.H.R contributed to the conceptualization and formatting of the article. N.S., H.M., S. S., A.P.R. and P.H.R. are responsible for writing, original draft preparation, and finalization of the manuscript. A.P.R and P.H.R. are responsible for funding acquisition.

Corresponding author

Correspondence to P. Hemachandra Reddy.

Ethics declarations

Ethics Approval

Not applicable

Consent to Participate

Not applicable

Consent to Publication

All authors agreed to publish the contents

Conflict of Interest

The authors declare no competing interests.

Research Involving Human Participants and/or Animals

Not applicable

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sawant, N., Morton, H., Kshirsagar, S. et al. Mitochondrial Abnormalities and Synaptic Damage in Huntington’s Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics. Mol Neurobiol 58, 6350–6377 (2021). https://doi.org/10.1007/s12035-021-02556-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02556-x

Keywords

Search

Navigation