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The Journal of Neuroscience, September 7, 2005, 25(36):8115-8121; doi:10.1523/JNEUROSCI.1143-05.2005

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Cellular/Molecular
Cdh1/Hct1-APC Is Essential for the Survival of Postmitotic Neurons

Angeles Almeida,^1,2 Juan P. Bolaños,² and Sergio Moreno³

¹Unidad de Investigación, Hospital Universitario de Salamanca, ²Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca and Centro Nacional de Investigaciones Cardiovasculares, and ³Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigacìones Científicas/Universidad de Salamanca, 37007 Salamanca, Spain

Cell division at the end of mitosis and G₁ is controlled by Cdh1/Hct1, an activator of the E3-ubiquitin ligase anaphase-promoting complex (APC) that promotes the ubiquitylation and degradation of mitotic cyclins and other substrates. Cdh1–APC is active in postmitotic neurons, where it regulates axonal growth and patterning in the developing brain. However, it remains unknown whether Cdh1–APC is involved in preventing cell-cycle progression in terminally differentiated neurons. To address this issue, we used the small hairpin RNA strategy to deplete Cdh1 in postmitotic neurons. We observed that Cdh1 silencing rapidly triggered apoptotic neuronal death. To investigate the underlying mechanism, we focused on cyclin B1, a major Cdh1–APC substrate. Our results demonstrate that Cdh1 is required to prevent the accumulation of cyclin B1 in terminally differentiated neurons. Moreover, by keeping cyclin B1 low, Cdh1 prevented these neurons from entering an aberrant S phase that led to apoptotic cell death. These results provide an explanation for the mechanism of cyclin B1 reactivation that occurs in the brain of patients suffering from neurodegenerative diseases, such as Alzheimer's disease.

Key words: neurodegeneration; cyclin B1; cell cycle; Cdh1/Hct1; APC; cell death

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Received March 23, 2005; revised June 24, 2005; accepted July 21, 2005.

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