title: Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1.
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 G1-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 G1-S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1.
authors.affiliation: Research Institute of the McGill University Health Center, Centre for Research in Neuroscience, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boudreau
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Després
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D018450:Disease Progression; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D018797:Cell Cycle Proteins; D016900:Neurofilament Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C051774:neurofilament protein H; D019938:Cyclin D1; C470429:SOD1 G37R protein, mouse; D013482:Superoxide Dismutase; D051360:Cyclin-Dependent Kinase 5; C495900:CDK4 protein, human; C495905:CDK5 protein, human; C495902:Cdk4 protein, mouse; C495906:Cdk5 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D008911:Minocycline