Published online before print July 13, 2007

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2007.070052v1 171/3/962    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liao, G. Articles by Bi, X. Search for Related Content PubMed PubMed Citation Articles by Liao, G. Articles by Bi, X.

Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070052

Accepted for publication May 15, 2007.

Article

Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1^-/- Mouse Brain

Guanghong Liao^*, Yueqin Yao, Jihua Liu, Zhang Yu, Simon Cheung^*, Ang Xie^*, Xiaoli Liang, and Xiaoning Bi^*@

From the Department of Basic Medical Sciences,* College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California; the Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California; the Electron Microscopy Core Laboratory, Shanghai Medical College of Fudan University, Shanghai, China; and the Department of Pathology, Beijing Military Medical College, Beijing, China

^@ To whom correspondence should be addressed. E-mail: xbi{at}westernu.edu.

	Abstract

Niemann-Pick type C (NPC) disease is an autosomal recessive disorder caused by mutations of NPC1 and NPC2 genes. Progressive neurodegeneration that accompanies NPC is fatal, but the underlying mechanisms are still poorly understood. In the present study, we characterized the association of autophagic-lysosomal dysfunction with cholesterol accumulation in Npc1^-/- mice during postnatal development. Brain levels of lysosomal cathepsin D were significantly higher in mutant than in wild-type mice. Increases in cathepsin D occurred first in neurons and later in astrocytes and microglia and were both spatially and temporally associated with intracellular cholesterol accumulation and neurodegeneration. Furthermore, levels of ubiquitinated proteins were higher in endosomal/lysosomal fractions of brains from Npc1^-/- mice than from wild-type mice. Immunoblotting results showed that levels of LC3-II were significantly higher in brains of mutant than wild-type mice. Combined LC3 immunofluorescence and filipin staining showed that LC3 accumulated within filipin-labeled cholesterol clusters inside Purkinje cells. Electron microscopic examination revealed the existence of autophagic vacuole-like structures and multivesicles in brains from Npc1^-/- mice. These results provide strong evidence that cholesterol accumulation-induced changes in autophagy-lysosome function are closely associated with neurodegeneration in NPC.

This article has been cited by other articles:

				S.-D. Ha, B. Ham, J. Mogridge, P. Saftig, S. Lin, and S. O. Kim Cathepsin B-mediated Autophagy Flux Facilitates the Anthrax Toxin Receptor 2-mediated Delivery of Anthrax Lethal Factor into the Cytoplasm J. Biol. Chem., January 15, 2010; 285(3): 2120 - 2129. [Abstract] [Full Text] [PDF]

				A. Amritraj, K. Peake, A. Kodam, C. Salio, A. Merighi, J. E. Vance, and S. Kar Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice Am. J. Pathol., December 1, 2009; 175(6): 2540 - 2556. [Abstract] [Full Text] [PDF]

				Q. Qin, M. Baudry, G. Liao, A. Noniyev, J. Galeano, and X. Bi A Novel Function for p53: Regulation of Growth Cone Motility through Interaction with Rho Kinase J. Neurosci., April 22, 2009; 29(16): 5183 - 5192. [Abstract] [Full Text] [PDF]

				C. D. Pacheco, M. J. Elrick, and A. P. Lieberman Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis Hum. Mol. Genet., March 1, 2009; 18(5): 956 - 965. [Abstract] [Full Text] [PDF]

				A. R. Alvarez, A. Klein, J. Castro, G. I. Cancino, J. Amigo, M. Mosqueira, L. M. Vargas, L. F. Yevenes, F. C. Bronfman, and S. Zanlungo Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease FASEB J, October 1, 2008; 22(10): 3617 - 3627. [Abstract] [Full Text] [PDF]

				H. Li, S. D. Turley, B. Liu, J. J. Repa, and J. M. Dietschy GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice J. Lipid Res., August 1, 2008; 49(8): 1816 - 1828. [Abstract] [Full Text] [PDF]

				S. E. Phillips, E. A. Woodruff III, P. Liang, M. Patten, and K. Broadie Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration J. Neurosci., June 25, 2008; 28(26): 6569 - 6582. [Abstract] [Full Text] [PDF]