Karten, Barbara - Dalhousie University - Department of Biochemistry & Molecular Biology

研究领域

Cholesterol homeostasis in the brain The brain contains 25% of cholesterol in the body, but comprises only about 5% of body weight. Since cholesterol cannot cross the blood-brain-barrier, the brain is responsible for synthesizing its own cholesterol. Imbalances in brain cholesterol homeostasis have been implicated in several neurodegenerative diseases. Niemann-Pick Type C disease Niemann-Pick type C disease (NPC) is a fatal neurodegenerative disorder, caused in 95% of cases by mutations in the NPC1 protein. A hallmark of NPC disease is the accumulation of cholesterol and other lipids in late endosomes and lysosomes. NPC1-deficient neurons segregate cholesterol in the cell body leading to a relative depletion of cholesterol in the axons. Our research is concerned with the consequences of NPC1 deficiency for the synapse, focusing on cholesterol distribution in the synapse, and a potential role of NPC1 in synaptic vesicle recycling. Cholesterol import into mitochondria Mitochondrial dysfunction is a common characteristic of many neurodegenerative diseases. Due to their high energy demand, neurons are particularly vulnerable to mitochondrial dysfunction. Cholesterol content of the mitochondrial membranes can influence membrane fluidity and protein function. Cholesterol also serves as the substrate for neurosteroids, which play a role in many processes in the brain, such as neuronal growth and differentiation. A second area of research in my lab therefore explores mechanisms of cholesterol import into mitochondria.

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Martin L.A., Kennedy B.E., and Karten B., (2016) Mitochondrial Cholesterol: Mechanisms of Import and Effects on Mitochondrial Function. J. Bioenerg. Biomembr. 48:137-151 [PubMed] [Article] Kennedy B.E., Hundert A.S., Goguen D., Weaver I.C.G., and Karten B., (2016) Pre-symptomatic alterations in amino acid metabolism and DNA methylation in the cerebellum of a murine model of Niemann-Pick Type C disease. Am. J. Pathol. 186:1582-1597 [PubMed] [Article] Vance J.E. and Karten B., (2014) Niemann-Pick C Disease and Mobilization of Lysosomal Cholesterol by Cyclodextrin J. Lipid Res. 55:1609-1621 [PubMed] [Article] Kennedy B.E., Madreiter C.T., Vishnu N., Malli R., Graier W.F., and Karten B., (2014) Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick Type C1-deficient cells. J. Biol. Chem. 289:16278-16289 [PubMed] [Article] Kennedy BE., LeBlanc VG., Mailman TM., Fice D., Burton I., Karakach TK., and Karten B, (2013) Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain PLoS One 8:e82658 [PubMed] [Article] Kennedy BE., Charman M., and Karten B., (2012) Niemann-Pick Type C2 protein contributes to the transport of endosomal cholesterol to mitochondrial without interacting with NPC1 J. Lipid Res. 12:2632-2642 [PubMed] [Article] Mailman, TM., Hariharan, M., and Karten B. , (2011) Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol. J. Neurochem. :Sept 7. Epub ahead of print, doi: 10.1111/j.1471-4159.2011.07474 [PubMed] Charman, M., Kennedy, B.E., Osborne, N. and Karten, B., (2010) MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein J. Lipid Res. 51:1023-1034 [PubMed] Hawes, CM., Wiemer, H., Krueger, SR., Karten, B., (2010) Presynaptic defects of NPC1-deficient hippocampal neurons are not directly related to plasma membrane cholesterol J. Neurochem. in press: [PubMed] Karten, B., Campenot R. B., Vance, D. E., and Vance, J. E. , (2006) Expression of ABCG1, but not ABCA1, correlates with cholesterol release from cerebellar astroglia J. Biol. Chem. 281:4049-4057 [PubMed] Karten, B., Campenot R. B., Vance, D. E., and Vance, J. E. , (2006) The Niemann-Pick Type C1 protein in recycling endosomes of pre-synaptic nerve terminals. J. Lipid Res. 47:504-514 [PubMed] Vance, JE., Karten, B. and Hayashi, H., (2006) Lipid dynamics in neurons Biochem. Soc. Trans. 34:399-403 [PubMed] Karten B., Hayashi H., Campenot R.B., Vance D.E., and Vance J.E. , (2005) Neuronal Models for Studying Lipid Metabolism and Transport. Methods 36:117-128 [PubMed] Paul C.A., Reid P.C., Boegle A.K., Karten B., Zhang M., Jiang Z.G, Franz D., Lin L., Chang T.Y., Vance J.E., Blanchette-Mackie J., and Maue R.A. , (2005) Adenovirus expressing an NPC1-GFP fusion gene corrects neuronal and nonneuronal defects associated with Niemann pick type C disease. J Neurosci Res. 86:706-719 [PubMed] Karten B., Hayashi H., Francis G.A., Campenot R.B., Vance D.E., and Vance J.E. , (2005) Generation and Function of Astroglial Lipoproteins from Niemann-Pick Type C1-deficient Mice. Biochem. J. 387:779-788 [PubMed] Vance J.E., Hayashi H., and Karten B., (2005) Cholesterol Homeostasis in Neurons and Glial Cells. Semin. Cell Dev. Biol. 16:193-212 [PubMed] Hayashi H., Karten B., Vance D.E., Campenot R.B., Maue R.A., Vance J.E. , (2004) Methods for the study of lipid metabolism in neurons. Anal. Biochem. 331:1-16 [PubMed] Choi H.Y., Karten B., Chan T., Vance J.E., Greer W.L., Heidenreich R.A., Garver W.S., Francis G.A. , (2003) Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease. J. Biol. Chem. 278:32569-32577 [PubMed] Karten B., Vance D.E., Campenot R.B., and Vance J.E., (2003) Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons. J. Biol. Chem. 278:4168-4175 [PubMed] Karten B., Vance D.E., Campenot R.B., and Vance J.E. , (2002) Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J. Neurochem. 83:1154-1163 [PubMed]