The Neuronal Expression of MYC Causes a Neurodegenerative Phenotype in a Novel Transgenic Mouse

Many different proteins associated with the cell cycle, Including cyclins, cyclin-dependent kinases, anti proto-oncogenes such as c-MYC (MYC), arc Increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery In neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, Including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC can be Induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results In neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results In neurodegeneration in vivo. Our current findings, coupled with those of previous reports, strengthen the hypothesis that neurodegeneration in Alzheimer's disease, similar to cellular proliferation in cancer, is a disease that results from inappropriate cell cycle control. (Am Pathol 2009 174:891-897; DOI: 10.2353/ajpath.2009.080583)