Myeloid cell leukemia sequence 1 (Mcl-1) is a pro-survival member of the Bcl-2 family, which is essential for neuronal development. Although Mcl-1 is known to have an oncogenic role in cancer, its contribution to neurological disorders has not been well studied. Now (p. 3023), Kumar Nikhil and Kavita Shah investigate the mechanism of Mcl-1 regulation under neurotoxic conditions in an Alzheimer's disease (AD) model. The authors identify Mcl-1 as a disease-specific target of Cdk5. They demonstrate that Mcl-1 levels determine the threshold for cellular damage in response to neurotoxic insults. Cdk5 phosphorylates Mcl-1 at T92, which triggers the ubiquitylation-mediated degradation of Mcl-1, resulting in mitochondrial dysfunction and neurotoxicity. Phosphorylation-resistant Mcl-1 protects cells from mitochondrial dysfunction, and overexpression of Mcl-1 is shown to be highly neuroprotective. To further examine the clinical significance of their findings, the authors use human clinical AD specimens and demonstrate that there is an inverse correlation between Mcl-1 levels and disease severity in AD pathogenesis. These findings unravel the mechanism by which Cdk5 deregulation leads directly to Mcl-1 degradation, resulting in neurotoxicity in a model of AD.
