title: The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, 2103 Cornell Rd., Cleveland, OH 44106, USA. hyoung-gon.lee@case.edu
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesus
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nunomura
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Sandy L
authors.initials: SL
authors.lastname: Richardson
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D002453:Cell Cycle; D005786:Gene Expression Regulation; D016259:Genes, myc; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000473:pathology; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction