Diane Merry

..These results demonstrate that some of the gene expression effects of expanded polyglutamine proteins occur independently of protein context...

..These data suggest that hormone-based therapies designed to treat SBMA patients, even with advanced disease, are likely to be effective...

..Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators...

..Whereas differences, primarily in neuropathological findings, exist in these models, these differences may be exploited to begin to elucidate the most relevant pathological features of KD...

..These results indicate that activation of the DAF-16/FOXO3a pathway, genetically or pharmacologically, confers protection against the known causes of motor neuron diseases...

..They also highlight a mechanistic basis for the requirement for nuclear localization in SBMA neurotoxicity, namely the lack of mutant AR removal by the autophagic protein degradation pathway...

..The recent development of useful animal and cell models of SBMA will lead to increased understanding of disease pathogenesis, as well as to the development of new and better therapeutic strategies...

..These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis...

..Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases...

..This model mimics the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA...

..Our findings indicate that therapeutic intervention to induce autophagy represents a potential potent benefit for SBMA, and that it likely does so by protecting SBMA motor neurons independent of a direct effect on mutant AR...

..Because of the central role the ubiquitin-proteasome degradation system plays in fundamental cellular processes, any alteration in its function could cause cell death, ultimately contributing to SBMA pathogenesis...

..This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA...

..The research proposed here should lead to a better understanding of the specific pathogenic mechanisms responsible for SBMA;these studies should lead, as well, to a better understanding of these other protein accumulation diseases. ..

..This project should also elucidate the pathogenesis of SBMA and may lead to effective treatment for this and other hereditary degenerative neurological disorders. ..

..The research proposed here should lead to a better understanding of the specific pathogenic mechanisms responsible for SBMA; these studies should lead, as well, to a better understanding of these other protein accumulation diseases. ..

..The research proposed here should lead to a better understanding of the specific pathogenic mechanisms responsible for SBMA; these studies should lead, as well, to a better understanding of these other protein accumulation diseases. ..

..All participants will be required to present posters. Priority will be given to women, minorities, and persons with disabilities when selecting participants. ..

..Since polyglutamine expansion has been shown to alter the catabolism of the mutant AR, the effect of subcellular localization on AR catabolism of the AR, as well as on its phosphorylation state will be investigated. ..