Silencing Cell-Cycle Reentry in Postmitotic Neurons

Once neurons differentiate, cell-cycle proteins are downregulated, seemingly locking the cell in G0 phase. This suggests very tight control of expression of these proteins. However, increasing evidence suggests that cell-cycle proteins can be reactivated and contribute to cell demise. For example, the Cdk1– cyclin B1 complex can be reactivated in Alzheimer’s disease. The E3-ubiquitin ligase anaphasepromoting complex (APC) marks mitotic cyclins such as B1 for degradation, and APC is activated by Cdh1 at the end of mitosis. Because Cdh1–APC remains active in postmitotic cells, Almeida et al. tested whether Cdh1 can keep cyclin B1 in check, thus preventing cell-cycle reentry. The answer seems to be yes. The authors silenced Cdh1 using a targeted small hairpin RNA (shRNA). Cdh1 silencing in differentiated neuroblastoma cells or postmitotic cortical neurons promoted cell-cycle reentry and produced apoptosis, whereas a cyclin B1-targeted shRNA increased the survival of these cells. In primary cortical neurons, Cdh1 overexpression also prevented -amyloid-induced apoptosis.