Calpain-Regulated p35/cdk5 Plays a Central Role in Dopaminergic Neuron Death through Modulation of the Transcription Factor Myocyte Enhancer Factor 2

• DOI: 10.1523/jneurosci.2875-05.2006
• Publication Date: 2006-01-11T22:20:11Z
• Authors: Patrice D. Smith; Matthew P. Mount; Raj Shree; Steve Callaghan; Ruth S. Slack; Hymie Anisman; Inez Vincent; Xuemin Wang; Zixu Mao; David S. Park
• Keywords: Mef2; MPTP; Cyclin-dependent kinase 5

The mechanisms underlying dopamine neuron loss in Parkinson's disease (PD) are not clearly defined. Here, we delineate a pathway by which dopaminergic induced 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) is controlled vivo . We reported previously that calpains play central required role after MPTP treatment. provide evidence the downstream effector of through cyclin-dependent kinase 5 (cdk5)-mediated modulation transcription factor myocyte enhancer 2 (MEF2). show MPTP-induced conversion cdk5 activator p35 to pathogenic p25 form dependent on calpain activity In addition, deficiency attenuates and behavioral outcome. Moreover, MEF2 phosphorylated Ser444, an inactivating site, This phosphorylation both activity, consistent with model calpain-mediated activation results Finally, critical for because “cdk5 site mutant” MEF2D provides neuroprotection mouse PD. Together, these data indicate calpain-p35-p25/cdk5-mediated inactivation plays