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| Dr. Schreiber's Research Description |
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Primary Research Interests The major focus of my laboratory is to elucidate the molecular mechanisms underlying selective neuronal degeneration, a major pathological feature of Alzheimer’s, Parkinson’s and other age-related neurodegenerative diseases. We employ state-of-the-art molecular, biochemical, immunohistochemical and histological techniques in animal and cell culture studies.] Research Approach p53 and neuronal degeneration: We have been studying the role of the p53 tumor suppressor gene in the central nervous system for several years. We were the first to show increased p53 expression and activation of p53 function in degenerating neurons. Until recently the mechanism whereby p53 accumulates in neurons was unknown. We recently discovered that p53 accumulates through decreased ubiquitination and proteasome-mediated degradation. This is a novel mechanism leading to p53 stabilization in multiple models of neuronal degeneration. Manipulation of ubiquitin expression as well as proteins that interact with p53 and target its ubiquitination may be neuroprotective. We are also studying the role of the nucleolus in neuronal apoptosis. In this regard we are investigating interactions between p53 and key nucleolar proteins relevant to neurodegeneration. Ubiquitin-proteasome dysfunction in the CNS: Dysfunction of the ubiquitin-proteasome pathway, resulting in the accumulation of abnormal ubiquitinated protein aggregates, has been strongly implicated in the pathogenesis of many neurodegenerative disorders. One way in which the ubiquitin-proteasome pathway may be impaired is through the adverse actions of a mutant form of ubiquitin, called Ub+1. Ub+1, produced by molecular misreading, accumulates in the brain of patients with Alzheimer's and other neurodegenerative diseases. We recently found that Ub+1 is neurotoxic through a mechanism that leads to impaired axonal transport and mitochondrial stress. In addition to studying the mechanism of Ub+1-induced neurotoxicity in more detail we are also generating transgenic mice that overexpress either Ub+1 or wild-type ubiquitin in neurons. Once available, these mice may provide insight into the role of impaired ubiquitin-proteasome processing in neuronal degeneration, and could lead to novel therapeutic approaches. Projects in Development: Projects that are currently in development include (1) applications of histone deacetylase inhibitors for neuroprotection, (2) effects of cerebral ischemia on mitochondrial axonal transport. |
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