Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

• DOI: 10.1242/jcs.108183
• Publication Date: 2012-08-17T00:26:31Z
• Authors: Kuei-Hua Chang; Fabien Vincent; Kavita Shah
• Keywords: CDC25A; Cdc25; Cyclin-dependent kinase 5; Hyperphosphorylation

Aberrant activation of cell cycle proteins is believed to play a critical role in Alzheimer's disease (AD) pathogenesis; although, the molecular mechanisms leading their diseased neurons remain elusive. The goal this study investigate mechanistic link between Cdk5 deregulation and re-activation Aβ1-42-induced neurotoxicity. Using chemical genetic approach, we identified Cdc25A, Cdc25B, Cdc25C as direct substrates mouse brain lysates. We show that deregulated directly phosphorylates at multiple sites, which not only increases phosphatase activities but also facilitates release from 14-3-3 inhibitory binding. turn activate Cdk1, Cdk2 Cdk4 kinases causing neuronal death. Selective inhibition abrogates Cdc25 Cdk activations Aβ1-42-treated neurons. Similarly, phosphorylation-resistant mutants sites are defective activating Cdk2, primary cortical neurons, underlining Cdk5-mediated major mechanism Cdks AD pathogenesis. These results were further confirmed human clinical samples displayed higher Cdc25B coincident with increased activity samples, compared age-matched controls. Inhibition confers highest neuroprotection against Aβ1-42 toxicity, while was partially neuroprotective, emphasizing decisive cycle-driven