Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin-dependent kinase 5 activation by p35 or p25.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Neurotoxicity mediated by glutamate is thought to play a role in the neuronal death through intracellular calcium-dependent signaling cascades. Cyclin-dependent kinase 5 (Cdk5) has been proposed as one of the calcium-dependent mediators that may cause neuronal death observed in this disease. Cdk5 is activated in neurons by the association with its activators, p35 or p39. The calcium-activated protease calpain cleaves p35 to its truncated product, p25, which eventually causes the cellular mislocalization and prolonged activation of Cdk5. This deregulated Cdk5 induces cytoskeletal disruption and apoptosis. To examine whether inhibition of the calpain-mediated conversion of p35 to p25 can delay the disease progression of ALS, we generated double transgenic mice in which ALS-linked mutant copper/zinc superoxide dismutase 1 (SOD1G93A) was expressed in a p35-null background. The absence of p35 neither affected the onset and progression of motor neuron disease in the mutant SOD1 mice nor ameliorated the pathological lesions in these mice. Our results provide direct evidence that the pathogenesis of motor neuron disease in the mutant SOD1 mice is independent of the Cdk5 activation by p35 or p25.
Takahashi
Satoru
S
Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kulkarni
Ashok B
AB
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D015996:Survival Rate
D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases