Ataxia telangiectasia (AT) is an autosomal recessive disease caused by mutation in ataxia telangiectasia mutated (ATM) gene. ATM, a protein kinase, is activated by DAN double strand break and in turn it activates DNA repair and cell cycle checkpoint mechanisms to maintain genomic stability. The loss of these functions of ATM explains many symptoms of AT such as predisposition to cancer, radiation sensitivity, and immunodeficiency. However, it is not clear how ATM loss triggers neurodegeneration, which causes ataxia (motor dysfunction) in AT. We recently found that ATM induces destabilizing phosphorylation of cyclin D1 on the Thr286 residue, and suppresses cyclin D1 expression. We have also found that the suppression of cyclin D1 plays a critical role in inducing a G1 checkpoint following DNA damage. We will examine the roles of ATM and cyclin D1 in neuronal cell death induced by DNA damage. Metabolic demand in neurons is considered to generate high levels of reactive oxygen species which damage DNA. ATM senses such damage and would activate cell cycle checkpoint and DNA repair mechanism to cope with such endogenous genotoxic stress. We hypothesized that when ATM deficient neurons are exposed to genotoxic stress, cyclin D1 expression continues because its Thr286 residue is not phosphorylated. The high expression of cyclin D1 would override the G1 checkpoint and contribute to accumulation of DNA lesions in proliferating neural cells (Aim 1). In postmitotic neurons, high cyclin D1 expression would trigger aberrant cell cycle progression and cell death (Aim 2).
In Aim 3, we will examine, if DNA lesions accumulated during proliferation would sensitize postmitotic neuron to DNA damaging treatment. Using primary neural cells from ATM-/- and +/+ mice, and human neural stem cells, we examine if ATM dependent cyclin D1 suppression protects neurons from oxidative stress. Biological consequence of genotoxic stress will be determined following manipulating the activity or expression of ATM and cyclin D1 using a specific inhibitor, shRNA or neutralizing antibody injection. The experiments are carefully designing to elucidate the validity of the novel concept that through its ability to control cyclin D1 expression, ATM plays a critical role in neuronal cells under genotoxic stress.
We have found that under DNA damaging condition, ATM (ataxia telangiectasia mutated) controls cell cycle progression at least in part by its ability to target cyclin D1. Appling this new concept of ATM-cyclin D1 dependent cell cycle regulation to the biology of the neurons, this proposal will address molecular mechanism of degeneration of neurons in ataxia telangiectasia (AT). The finding obtained from these studies may advance our fundamental understanding on pathogenesis of AT, as well as other related neurodegenerative diseases, such as brain stroke, Parkinson disease, and Alzheimer's disease.
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