The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse

Hyoung Gon Lee, Gemma Casadesus, Akihiko Nunomura, Xiongwei Zhu, Rudy J. Castellani, Sandy L. Richardson, George Perry, Dean W. Felsher, Robert B. Petersen, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are 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.

Original languageEnglish
Pages (from-to)891-897
Number of pages7
JournalAmerican Journal of Pathology
Volume174
Issue number3
DOIs
StatePublished - Mar 2009
Externally publishedYes

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