Modifiers of Huntingtin and Alpha-synuclein Toxicity

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DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant inherited disorder characterized by involuntary movements, personality changes and dementia, and is caused by an expansion of a CAG/polyglutamine repeat in the IT-15 gene. A major neuropathological hallmark in HD is the occurrence of intranuclear and cytoplasmic inclusion bodies that contain huntingtin (the protein encoded by IT-15). Cytoplasmic inclusion bodies (Lewy bodies) are also a prominent nature of Parkinson's disease (PD), a neurodegenerative disorder characterized by muscle rigidity, bradykinesia, resting tremor and postural instability. Lewy bodies are composed primarily of the protein alpha-synuclein, and two point mutations in the alpha-synuclein gene cause early-onset, inherited forms of Parkinson's disease. Alpha-synuclein and huntingtin aggregate into ordered fibrillar structures with properties characteristic of amyloid. The 'amyloid hypothesis', developed originally to describe the role of beta-amyloid in Alzheimer's Disease (AD), suggests that the aggregation of proteins into an ordered fibrillar structure is causally related to aberrant protein interactions that culminate in neuronal dysfunction and cell death (Hardy and Selkoe, 2002). The precise roles of protein aggregation, amyloid formation and inclusion bodies in neurodegeneration remain controversial, and it is not yet clear if common molecular mechanisms underlie HD and Parkinson's disease. We have used yeast as a model eukaryotic organism to test the hypothesis that the downstream targets and molecular mechanisms by which huntingtin and ot-synuclein mediate toxicity are unique. Using a genome-wide screening approach in yeast we isolated 52 genes that modify huntingtin toxicity, and 86 genes that modify alpha-synuclein toxicity. 30% of genes that affect huntingtin toxicity are enriched in the functionally related categories of protein folding and cell stress, while 29% of genes that modify alpha-synuclein toxicity are involved in vesicular transport and lipid metabolism. Our preliminary results indicate surprisingly that the genes and cellular pathways that modulate huntingtin and alpha-synuclein toxicity in yeast are completely divergent. Nearly half of the genes we isolated are annotated as having one or more human ortholog, suggesting we may have discovered in yeast conserved cell-biological response pathways to huntingtin and alpha-synuclein that are relevant to HD and Parkinson's disease. Using the resources and information that we have generated, we now wish to advance our understanding of the neurodegeneration that occurs in HD and PD by applying molecular genetic and biochemical techniques to validate (or invalidate) the genetic modifiers we have identified. Our long-term goal is to use the information we gain in these studies to test hypotheses in animal models of HD and Parkinson's disease.