Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.
Recent studies suggest that increased activity of cyclin-dependent kinase 5 (Cdk5) may contribute to neuronal death and cytoskeletal abnormalities in Alzheimer's disease. We report here such deregulation of Cdk5 activity associated with the hyperphosphorylation of tau and neurofilament (NF) proteins in mice expressing a mutant superoxide dismutase (SOD1(G37R)) linked to amyotrophic lateral sclerosis (ALS). A Cdk5 involvement in motor neuron degeneration is supported by our analysis of three SOD1(G37R) mouse lines exhibiting perikaryal inclusions of NF proteins. Our results suggest that perikaryal accumulations of NF proteins in motor neurons may alleviate ALS pathogenesis by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates.
Nguyen
M D
MD
Centre for Research in Neurosciences, McGill University, Research Institute of the McGill University, Health Centre, H3G 1A4, Montreal, Quebec, Canada.
Larivière
R C
RC
Julien
J P
JP
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D002479:Inclusion Bodies / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000002:abnormalities / Q000378:metabolism; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000502:physiology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D013482:Superoxide Dismutase; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases