+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model

, : Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. Journal of Neuroscience 22(15): 6515-6525

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.


PMID: 12151531

DOI: 20026692

Other references

Lelis, I.I., 1984: Staphylococcal and toxic "burned skin" syndromes. Vestnik Dermatologii i Venerologii: 47-49

Sugano, N.; Ito, K., 2000: Nicotine switches the form of H2O2-induced cell death from apoptosis to necrosis in U937 cells. Cigarette smoking is a major risk factor for lung diseases and oral diseases. The present study examined the effect of nicotine on H(2)O(2)-induced apoptosis in U937 cells. In the presence of 1 microg/ml nicotine, cell viability was not affected,...

Baxter, Mr, 1987: Implications of behaviour studies on the development of housing systems. BSAP occasional ication: an occasional ication of the British Society of Animal Production: 1) 99-102

Hay Roe Hugh, 1995: How readable is your writing?. The Professional Geologist 32(8): 26

Omar, H.R.; Mirsaeidi, M.; Bosco, G.; Morgan, K.; Dalvi, P.; Helal, E.; Mangar, D.; Camporesi, E.M., 2016: Cardiovascular complications and mortality determinants in near drowning victims: A 5-year retrospective analysis. Journal of Critical Care: -

McCarty, M., 1947: The Occurrence During Acute Infections Of A Protein Not Normally Present In The Blood : Iv. Crystallization Of The C-Reactive Protein. A procedure is described for the isolation and crystallization from human serous fluids of the C-reactive protein, a substance which appears in the blood especially in the early phase of certain acute infectious diseases. Immunological studies con...

Stanford, J.R.; Carpenter, C.B.; Detore, A., 2013: Excellence in patient outcomes as well as hospital performance on process measures: we can do both. Quality Management in Health Care 22(1): 62-65

Jiao Zun Sheng; Fritsche A.E.gene, 1994: Depositional environments and paleogeography of the Coldwater Formation, upper Sespe Creek, Ventura County, California. Book - Pacific Section, SEPM (Society for Sedimentary Geology) 74: 57-78

Isogai, Yukihiro; Ishida, Hideharu; Kiso, Makoto; Hasegawa, Akira, 1996: Synthetic studies on sialoglycoconjugates 95: Total synthesis of sulfated glucuronyl lactosaminyl paraglobosides. 3-O-Sulfo glucuronyl neolactohexanosyl ceramide derivatives (heptasaccharides) have been synthesized. Condensation of 2-(trimethylsilyl)ethyl 2,4,6-tri-O-benzyl-beta-D-galactopyranoside (2) with 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-phthalimido-bet...

Skotnicki, A.B., 1978: Biological activity and physico-chemical properties of TFK thymic extract. Polski Tygodnik Lekarski 33(28): 1119-1122