Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.

Additional Metadata
Keywords 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, Neurodegeneration
Persistent URL dx.doi.org/10.1073/pnas.2232515100
Journal Proceedings of the National Academy of Sciences of the United States of America
Citation
Smith, P, Crocker, S.J. (Stephen J.), Jackson-Lewis, V. (Vernice), Jordan-Sciutto, K.L. (Kelly L.), Hayley, S, Mount, M.P. (Matthew P.), … Park, D.S. (David S.). (2003). Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America, 100(23), 13650–13655. doi:10.1073/pnas.2232515100