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, 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.
Lee
Hyoung-gon
HG
Department of Pathology, Case Western Reserve University, 2103 Cornell Rd., Cleveland, OH 44106, USA. hyoung-gon.lee@case.edu
Casadesus
Gemma
G
Nunomura
Akihiko
A
Zhu
Xiongwei
X
Castellani
Rudy J
RJ
Richardson
Sandy L
SL
Perry
George
G
Felsher
Dean W
DW
Petersen
Robert B
RB
Smith
Mark A
MA
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