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The Journal of Neuroscience, January 11, 2006, 26(2):440-447; doi:10.1523/JNEUROSCI.2875-05.2006

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

Patrice D. Smith,¹ Matthew P. Mount,¹ Raj Shree,¹ Steve Callaghan,¹ Ruth S. Slack,¹ Hymie Anisman,² Inez Vincent,³ Xuemin Wang,⁴ Zixu Mao,^4,5 and David S. Park¹

¹Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8M5, ²Neuroscience Institute, Carleton University, Ottawa, Ontario, Canada K1S 5B6, ³Department of Pathology, University of Washington, Seattle, Washington 98195, and Departments of ⁴Pharmacology and ⁵Neurology, Emory University School of Medicine, Atlanta, Georgia 30322

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

Key words: cyclin-dependent kinase 5; cdk5; myocyte enhancer factor 2; MEF2; dopamine; substantia nigra; Parkinson's disease; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP

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Received July 13, 2005; revised November 7, 2005; accepted November 8, 2005.

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