Defective cholesterol traffic and neuronal differentiation in neural stem cells of Niemann–Pick type C disease improved by valproic acid, a histone deacetylase inhibitor

• Published in: Biochemical and biophysical research communications 2007-08, Vol.360 (3), p.593-599
• Main Authors: Kim, Sun-Jung, Lee, Bong-Hee, Lee, Yong-Soon, Kang, Kyung-Sun
• Format: Article
• Language: English
• Subjects: A histone deacetylase inhibitor; Animals; Biological Transport - drug effects; Biological Transport - genetics; Cell Differentiation - drug effects; Cells, Cultured; Cholesterol - metabolism; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Histone Deacetylase Inhibitors; Mice; Neural stem cells; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Niemann-Pick Diseases - metabolism; Niemann–Pick type C disease; Proteins - genetics; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; Valproic Acid - pharmacology; Valproic acids
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.06.116

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.