Published online before print July 13, 2007

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(American Journal of Pathology. 2007;171:962-975.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070052

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

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.

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