IDENTIFICATION OF GENERIC SUPRESSORS OF PROTEINOPATHIES

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We aim to identify genes that reduce the toxicity of a wide range of different mutant proteins that cause neurodegeneration. We will identify such genes and pathways by performing a bioinformatics analysis of existing genetic screens for modifiers in lower organisms (from yeast to Drosophila), as well as targeted studies in all systems, including high confidence genome wide association study hits for Alzheimer's and Parkinson's disease and ALS. Using multiple data sources, we will identifyhallmark features of "generic modifiers" and use computational methods to identifynew modifiers, which will then be tested for efficacy in fruit fly models of different diseases, like Huntington's disease and forms of dementia. Novel modifiers showing efficacy in morethan one disease will be studied in cell models and fruit flies to identify mechanisms ofaction. The identification of such "generic" supressors and their mechanisms wouldcreate a list of high priority targets for consideration for therapeutic development and/ordetailed mechanistic analyses, as these would be acting on a range of diseases and areexpected to affect core processes.