Affiliation:
1. Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
Abstract
Cdk5 deregulation is highly neurotoxic in AD. We identified Mcl-1 as a direct Cdk5 substrate using an innovative chemical screen in mouse brain lysates. Our data demonstrate that Mcl-1 levels determine the threshold for cellular damage in response to neurotoxic insults. Mcl-1 is a disease-specific target of Cdk5, which associates with Cdk5 under basal conditions, however, is not regulated by it. Neurotoxic insults hyperactivate Cdk5 causing Mcl-1 phosphorylation at T92. This phosphorylation event triggers Mcl-1 ubiquitylation, which directly correlates with mitochondrial dysfunction. Consequently, ectopic expression of phosphorylation-dead T92A-Mcl-1 fully prevents mitochondrial damage and subsequent cell death triggered by neurotoxic treatments in neuronal cells and primary cortical neurons. Notably, enhancing Mcl-1 levels offer comparable neuroprotection as observed upon Cdk5 depletion, suggesting that Mcl-1 degradation by direct phosphorylation is a key mechanism by which Cdk5 promotes neurotoxicity in AD. The clinical significance of Mcl-1-Cdk5 axis was investigated in AD clinical specimens, which revealed an inverse correlation between Mcl-1 levels and disease severity. These results emphasize the potential of Mcl-1 upregulation as an attractive therapeutic strategy for delaying or preventing neurodegeneration in AD.
Funder
National Institute on Aging
Publisher
The Company of Biologists
Cited by
21 articles.
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