NPC1 gene deficiency leads to lack of neural stem cell self-renewal and abnormal differentiation through activation of p38 MAP kinase signaling

¹ Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, Korea
² Department of Anatomy and Neurobiology, College of Medicine, Cheju National University, Cheju, Korea
³ Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi, Japan

^* To whom correspondence should be addressed. E-mail: kangpub{at}snu.ac.kr.

	Abstract

Neural stem cells (NSC) are capable of giving rise to neurons, glia- and astrocytes. Although self renewal and differentiation in neural stem cells are regulated by many genes such as Notch, Numb etc., little is known of the role of defective genes on the self renewal and differentiation of neural stem cell from developing brain. The Niemann-Pick type C1 (NPC1) disease is one of the neurodegenerative diseases, caused by a mutation of NPC1 gene which affects the function of NPC1 protein. The ability of NSC self renewal and differentiation was investigated using a model of Niemann-Pick type C1 (NPC1) disease. The NPC1 disorder significantly affected the self renewal ability of neural stem cells, as well as the differentiation. Neural stem cell from NPC1^-/- mice showed impaired self renewal ability when compared to the NPC1^+/+ mice. These alterations were accompanied by the enhanced activity of p38 MAP kinases. Further, the specific p38 MAP kinase inhibitor, SB202190 improved the self renewal ability of NSCs from NPC^-/- mice. This indicated that the NPC1 deficiency can lead to lack of self renewal and altered differentiation of neural stem cells mediated by the activation of p38 MAP kinase impairing the generation of neurospheres from NPC1^-/-. Thus the NPC1 gene may play a crucial role in NSC self-renewal associated with p38 MAP kinase.