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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Oliver, Eugene J
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University of Washington
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Sancenon, Vicente; Lee, Sue-Ann; Patrick, Christina et al. (2012) Suppression of ?-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context. Hum Mol Genet 21:2432-49
Tauber, Eran; Miller-Fleming, Leonor; Mason, Robert P et al. (2011) Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity. J Biol Chem 286:410-9
Sathasivam, Kirupa; Lane, Amin; Legleiter, Justin et al. (2010) Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington's disease. Hum Mol Genet 19:65-78
Lotz, Gregor P; Legleiter, Justin; Aron, Rebecca et al. (2010) Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J Biol Chem 285:38183-93
Schwarcz, Robert; Guidetti, Paolo; Sathyasaikumar, Korrapati V et al. (2010) Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease. Prog Neurobiol 90:230-45
Legleiter, Justin; Mitchell, Emily; Lotz, Gregor P et al. (2010) Mutant huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J Biol Chem 285:14777-90
Legleiter, Justin; Lotz, Gregor P; Miller, Jason et al. (2009) Monoclonal antibodies recognize distinct conformational epitopes formed by polyglutamine in a mutant huntingtin fragment. J Biol Chem 284:21647-58
Wacker, Jennifer L; Huang, Shao-Yi; Steele, Andrew D et al. (2009) Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. J Neurosci 29:9104-14
Muccioli, Giulio G; Sia, Angela; Muchowski, Paul J et al. (2009) Genetic manipulation of palmitoylethanolamide production and inactivation in Saccharomyces cerevisiae. PLoS One 4:e5942
Rosser, Meredith F N; Washburn, Erin; Muchowski, Paul J et al. (2007) Chaperone functions of the E3 ubiquitin ligase CHIP. J Biol Chem 282:22267-77

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