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• W2160985655 abstract "There is growing evidence for involvement of members of the cyclin-dependent kinase (Cdk) family in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults. After our recent report that a deregulation of Cdk5 activity by p25 may contribute to pathogenesis of amyotrophic lateral sclerosis (ALS), we further examined the possible involvement of other Cdks in mice expressing a mutant form of superoxide dismutase (SOD1 G37R ) linked to ALS. No substantial changes in Cdk2 or Cdk6 distribution and kinase activities were detected in spinal motor neurons from SOD1 G37R mice when compared with normal mice. Of particular interest was the upregulation and mislocalization of Cdk4, a regulator of the G 1 -S checkpoint of the cell cycle, in motor neurons of SOD1 G37R mice. The increase of Cdk4 activity in SOD1 G37R mice was associated with an increase in nuclear Cdk4, cyclin D1, its coactivator, and with the abnormal phosphorylation of the retinoblastoma (Rb) protein at Cdk phosphorylation sites. Pharmacological treatment of SOD1 G37R mice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb. Interestingly, phospho-Rb was immunoprecipitated with anti-Cdk4 but not with anti-Cdk5 antibodies, suggesting a key role for Cdk4 in the phosphorylation of Rb. Remarkably, the overexpression of a transgene coding for human neurofilament H, a phosphorylation sink for deregulated Cdk5 activity by p25, resulted in a reduction in levels of nuclear Cdk4 and Rb phosphorylation. These results indicate that a cell cycle signaling at the neuronal G 1 -S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1." @default.
• W2160985655 created "2016-06-24" @default.
• W2160985655 creator A5001972907 @default.
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• W2160985655 date "2003-03-15" @default.
• W2160985655 modified "2023-09-23" @default.
• W2160985655 title "Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1" @default.
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• W2160985655 doi "https://doi.org/10.1523/jneurosci.23-06-02131.2003" @default.
• W2160985655 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6741997" @default.
• W2160985655 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/12657672" @default.
• W2160985655 hasPublicationYear "2003" @default.
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