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Previous Article | Next Article
The Journal of Neuroscience, August 1, 2002, 22(15):6515-6525
Deregulation of cdk5, Hyperphosphorylation, and Cytoskeletal Pathology in the Niemann-Pick Type C Murine Model
Bitao Bu1, 2, Jin Li1, Peter Davies3, and Inez Vincent1 1 Department of Pathology, University of Washington, Seattle, Washington 98195, 2 Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, 430030 Wuhan, China, and 3 Departments of Neuroscience and Pathology, Albert Einstein College of Medicine, New York, New York 10461
NPC-1 gene mutations cause Niemann-Pick type C (NPC), a neurodegenerative storage disease resulting in premature death in humans. Spontaneous mutation of the NPC-1 gene in mice generates a similar phenotype, usually with death ensuing by 12 weeks of age. Both human and murine NPC are characterized neuropathologically by ballooned neurons distended with lipid storage, axonal spheroid formation, demyelination, and widespread neuronal loss. To elucidate the biochemical mechanism underlying this neuropathology, we have investigated the phosphorylation of neuronal cytoskeletal proteins in the brains of npc-1 mice. A spectrum of antibodies against phosphorylated epitopes in neurofilaments (NFs) and MAP2 and tau were used in immunohistochemical and immunoblotting analyses of 4- to 12-week-old mice. Multiple sites in NFs, MAP2, and tau were hyperphosphorylated as early as 4 weeks of age and correlated with a significant increase in activity of the cyclin-dependent kinase 5 (cdk5) and accumulation of its more potent activator, p25, a proteolytic fragment of p35. At 5 weeks of age, the development of axonal spheroids was noted in the pons. p25 and cdk5 coaccumulated with hyperphosphorylated cytoskeletal proteins in axon spheroids. These various abnormalities escalated with each additional week of age, spreading to other regions of the brainstem, basal ganglia, cerebellum, and eventually, the cortex. Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC. The npc-1 mouse is a valuable in vivo model for determining how and when cdk5 becomes deregulated and whether cdk5 inhibitors would be useful in blocking NPC neurodegeneration.
Key words: cdk5; p35; neurodegeneration; Niemann-Pick disease type C; cholesterol; axon spheroid; lipid rafts; caveolas; neurofilament phosphorylation; tau phosphorylation; cytoskeletal pathology
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156515-11$05.00/0
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