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Smith PD, Mount MP, Shree R, Callaghan S, Slack RS, Anisman H, Vincent I, Wang X, Mao Z, Park DS. Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci. 2006 Jan 11;26(2):440-7. PubMed.
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Picower Institute of MIT
Comment by Lily Y. Moy and Li-Huei Tsai
A novel role for Cdk5 in dopaminergic neuronal loss has been added to a growing list of neurodegenerative conditions in which dysregulation of Cdk5 is thought to function. Accumulation of p25, a calpain cleavage product of the Cdk5-binding partner p35, has been implicated in Alzheimer disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and transient forebrain ischemia. However, there are few studies that have convincingly shown the in-vivo generation of p25 under neurotoxic conditions. Data from the lab of David Park at Ottawa Health Research Institute provide evidence that a neurotoxic regimen of the mitochondrial complex I inhibitor, MPTP, in mice results in the calpain-dependent generation of p25 in the substantia nigra.
This article reports that nigral p25 levels and Cdk5 activity increase following MPTP administration. The authors offer compelling data that the calpain-mediated cleavage of p35 to p25 contributes to MPTP-induced damage by using multiple parameters to assay nigral cell loss and striatal nerve terminal damage. Remarkably, the cell loss and striatal terminal damage resulting from MPTP treatment is attenuated in p35-/- mice. Similar findings were observed in mice that received an intrastriatal injection of an adenovirus overexpressing calpastatin, an endogenous inhibitor of calpain, lending further support to their model that MPTP activates Cdk5 via a calpain-dependent mechanism.
Interestingly, the authors also found that following MPTP treatment, phosphorylation of the transcription factor and Cdk5 substrate MEF2D is up-regulated, which results in inactivation of the transcription factor. In p35-/- mice and in mice overexpressing calpastatin, this MPTP-induced phosphorylation of MEF2D is attenuated, which may contribute to the neuroprotective effects via MEF2D-mediated survival signals. It is possible that other downstream targets of Cdk5 also play a role in MPTP-induced neurotoxicity, and future studies will need to address this possibility.
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