Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder in which premature loss of upper and lower motor neurons leads to fatal paralysis with a typical disease course of one to five years. Starting from 2006 with the identification of TDP-43 as the major protein component of the ubiquitinated inclusions occurring in affected neurons of ALS and Frontotemporal Lobar Dementia (FTLD) patients, there has been what is widely recognized to be a paradigm-shifting breakthrough in our understanding of neurodegeneration. Indeed, it has now been established that TDP-43, an RNA-binding protein that is normally localized mainly in the nucleus, forms cytoplasmic aggregates, which alter its subcellular localization in a variety of different neurodegenerative conditions, including ALS, FTLD, Alzheimer's and Parkinson's disease. In addition, identification of ALS-causing mutations not only in TDP-43, but more recently, also in another RNA-binding protein, namely FUS/TLS, confirmed the primary role of these proteins in the pathogenesis of ALS. Furthermore, these discoveries solidified the message of a key contribution of RNA-processing alterations to mechanisms of neurodegeneration. I plan to define a set of disease-relevant TDP-43- and/or FUS/TLS-dependent RNA-processing alterations. I propose to utilize existing transgenic mouse lines along with newly developed methodologies including high-throughput sequencing and induced pluripotent stem (iPS) cells to 1) determine the role of TDP-43 and FUS/TLS in the regulation of RNA metabolism in the normal central nervous system in mice, 2) identify RNA-processing alterations caused by expression of TDP-43 and FUS/TLS carrying disease-causing mutations in transgenic mice, 3) test the RNA-processing changes found in mice, in human motor neurons produced from iPS cells, and 4) identify the mechanisms underlying the observed disease-related RNA-processing alterations and test the efficacy of blocking compounds on the defined mechanisms in cell culture and mouse models.
Statement of Relevance to Public Health Amyotrophic Lateral Sclerosis, also called 'Lou Gehrig's disease', is a devastating disease causing muscle weakness progressing to paralysis and death within 1-5 years from diagnosis. There are no effective treatments for this disease that affects 1 in approximately 55,000 people in USA every year. The proposed work will contribute to our understanding of the chain of events leading to this disease and to uncover targets for therapeutic interventions.
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