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. (Am J Pathol

Control of Vertebrate Development by MYC

“…But even in postmitotic cells, MYC can induce cell-cycle entry and proliferation. For example, in vivo forced expression of MYC in postmitotic skin keratinocytes, forebrain neurons, adult myocytes, and support cells of adult utricles, led to their reentry into the cell cycle (Pelengaris et al 1999;Xiao et al 2001;Lee et al 2009;Burns et al 2012). However, while adenoviral-mediated expression of MYCN in cultured postmitotic sympathetic neurons also supported cell-cycle reentry, its expression in postmitotic cortical neurons failed to induce S-phase entry or progression (Wartiovaara et al 2002).…”

Cell cycle aberrations in Alzheimer’s disease: a novel therapeutic opportunity

“…Preclinically, testing may either be conducted in a broad array of well-characterized models of neurodegeneration, or in specific models of cell cycle-mediated neuronal loss [8,9]. Greater confidence might be generated by success according to both approaches.…”

“…This implies broad support for the cell cycle hypothesis. Furthermore, a transgenic mouse model with conditional and neuron-specific expression of c-Myc, a proto-oncogene that is increased in the vulnerable neurons in Alzheimer's disease [11], drives fully differentiated neurons to re-enter the cell cycle and causes cognitive deficits and neurodegeneration, indicating that cell cycle re-entry and [9]. This, or other, animal models may be useful not only for testing the cell cycle hypothesis and downstream mechanisms, but also as a tool for testing the potential therapeutics targeting cell cycle pathways in neurodegenerative diseases.…”

“…The consequence of this dysregulation is aberrant intra cellular metabolism, responsible for both the derangement of amyloid and tau processing, and the failure of neuronal function. Indeed, we recently demonstrated that the reactivation of cell cycle in adult neurons, either in vitro [8] or in vivo [9], caused a host of Alzheimer's-type changes, including neuro degeneration, suggesting the causal role of cell cycle re-entry in Alzheimer's disease.…”

Late phase cell cycle proteins in Alzheimer’s disease: a possible target for therapy?

“…A shift has been recently introduced i.e., after on only concentrating on Aβ and Tau as the only causative agents for AD, researchers explored the notion that there must be a more fundamental underlining mechanisms, such as inflammatory processes mediated by astrocytes and microglia [2][3][4] which then in coordination with Aβ and Tau deregulates the neuronal cell, thus leading to cell cycle activation [4,5]. Neuronal responses to such insults in AD brain include increased protein levels and immunoreactivity for kinases known to regulate cell cycle progression and consequently cell death [4,[6][7][8][9][10].…”