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: Sun-Jung Kim, Bong-Hee Lee, Yong-Soon Lee, Kyung-Sun Kang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 360 Issue 3 Pg. 593-9 (Aug 31 2007) ISSN: 0006-291X [Print] United States
• PMID: 17624314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Intracellular Signaling Peptides and Proteins
• Niemann-Pick C1 Protein
• Npc1 protein, mouse
• Proteins
• Valproic Acid
• Cholesterol

Topics

• Animals
• Biological Transport (drug effects, genetics)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Cholesterol (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Intracellular Signaling Peptides and Proteins
• Mice
• Neurons (drug effects, metabolism, pathology)
• Niemann-Pick C1 Protein
• Niemann-Pick Diseases (metabolism)
• Proteins (genetics)
• Stem Cells (drug effects, metabolism, pathology)
• Valproic Acid (pharmacology)