p35/p25 is not essential for tau and cytoskeletal pathology or neuronal loss in Niemann-Pick type C disease.
Hyperactivation of the cyclin-dependent kinase 5 (cdk5), triggered by proteolytic conversion of its neuronal activator, p35, to a more potent byproduct, p25, has been implicated in Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Niemann-Pick type C disease (NPC). This mechanism is thought to lead to the development of neuropathological hallmarks, i.e., hyperphosphorylated cytoskeletal proteins, neuronal inclusions, and neurodegeneration, that are common to all three diseases. This pathological ensemble is recapitulated in a single model, the npc-1 (npc(-/-)) mutant mouse. Previously, we showed that pharmacological cdk inhibitors dramatically reduced hyperphosphorylation, lesion formation, and locomotor defects in npc(-/-) mice, suggesting that cdk activity is required for NPC pathogenesis. Here, we used genetic ablation of the p35 gene to examine the specific involvement of p35, p25, and hence cdk5 activation in NPC neuropathogenesis. We found that lack of p35/p25 does not slow the onset or progression or improve the neuropathology of NPC. Our results provide direct evidence that p35/p25-mediated cdk5 deregulation is not essential for NPC pathology and suggest that similar pathology in AD may also be cdk5 independent.
Hallows
Janice L
JL
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Iosif
Robert E
RE
Biasell
Rebecca D
RD
Vincent
Inez
I
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000172:deficiency / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000502:physiology; D056427:t-Complex Genome Region; D016875:tau Proteins / Q000378:metabolism*
C492236:Cdk5r1 protein, mouse; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D016875:tau Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D010751:Phosphopyruvate Hydratase