title: Defective cholesterol traffic and neuronal differentiation in neural stem cells of Niemann-Pick type C disease improved by valproic acid, a histone deacetylase inhibitor.
abstract: Niemann-Pick type C disease (NPC) is a neurodegenerative and lipid storage disorder for which no effective treatment is known. We previously reported that neural stem cells derived from NPC1 mice showed impaired self-renewal and differentiation. We examined whether valproic acid (VPA), a histone deacetylase inhibitor, could enhance neuronal differentiation and recover defective cholesterol metabolism in neural stem cells (NSCs) from NPC1-deficient mice (NPC1(-/-)). VPA could induce neuronal differentiation and restore impaired astrocytes in NSCs from NPC1(-/-) mice. Importantly, an increasing level of cholesterol within NSCs from NPC1(-/-) mice could be reduced by VPA. Moreover, essential neurotrophic genes (TrkB, BDNF, MnSoD, and NeuroD) were up-regulated through the repression of the REST/NRSF and HDAC complex by the VPA treatment. Up-regulated neurotrophic genes were able to enhance neural differentiation and cholesterol homeostasis in neural stem cells from NPC1(-/-) mice. In this study, we suggested that, along with cholesterol homeostasis, impaired neuronal differentiation and abnormal morphology of astrocytes could be rescued by the inhibition of HDAC and REST/NRSF activity induced by VPA treatment.
authors.affiliation: Adult Stem Cell Research, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Bong-Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Yong-Soon
authors.initials: YS
authors.lastname: Lee
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D014635:Valproic Acid; D002784:Cholesterol