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Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1.
Nguyen, MD; Boudreau, M; Kriz, J; Couillard-Després, S; Kaplan, DR; Julien, JP;
J Neurosci. 2003; 23(6):2131-2140
Originalarbeiten (Zeitschrift)


Couillard-Després Sébastien


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.

Useful keywords (using NLM MeSH Indexing)

Amino Acid Substitution

Amyotrophic Lateral Sclerosis/genetics*

Amyotrophic Lateral Sclerosis/metabolism*

Amyotrophic Lateral Sclerosis/pathology


Anti-Bacterial Agents/pharmacology

Cell Cycle Proteins/metabolism*

Cell Death

Cell Nucleus/metabolism

Cyclin D1/metabolism

Cyclin-Dependent Kinase 4

Cyclin-Dependent Kinase 5

Cyclin-Dependent Kinases/metabolism

Disease Progression

G1 Phase/physiology



Mice, Neurologic Mutants

Mice, Transgenic


Motor Neurons/drug effects

Motor Neurons/metabolism*

Motor Neurons/pathology

Neurofilament Proteins/biosynthesis

Neurofilament Proteins/genetics

Phosphorylation/drug effects

Proto-Oncogene Proteins*

Retinoblastoma Protein/metabolism

S Phase/physiology

Signal Transduction

Superoxide Dismutase/biosynthesis*

Superoxide Dismutase/genetics



Find related publications in this database (Keywords)

amyotrophic lateral sclerosis
Cu/Zn superoxide dismutase
cyclin-dependent kinase
cell cycle
neuronal apoptosis
transgenic mice