A key characteristic in numerous neurodegenerative diseases is the accumulation of amyloid- like aggregates. Although this topic has been highly studied, major controversy still surrounds the question of whether these amyloid inclusions cause the disease or represent a manifestation of a cytoprotective mechanism. Thus to gain an understanding of defense mechanisms against protein aggregation diseases, it is necessary to define the pathway by which amyloid-like aggregation occurs and how this process is regulated. Huntingtin (Htt), the disease associated protein in Huntington's disease (HD), will be used in order to study a cellular pathway for protection against aggregation prone cytotoxic proteins. This study will be carried out utilizing a Saccharomyces cerevisiae model of HD. Yeast is a reliable and useful model to study HD because key characteristics of the disease such as Htt inclusions and polyQ length dependent toxicity are recapitulated. Furthermore, a vast number of cellular processes are conserved from yeast to mammals thus making it a suitable organism in which to identify components of a pathway. Preliminary data in our lab from a screen for novel suppressors of Htt toxicity suggest a vital role for aggregation in the inhibition of toxicity. Several Q-rich proteins as well as an Hsp70/Hsp90 co-chaperone each suppress toxicity associated with an extended polyQ Htt fragment (Htt103Q) in yeast. This toxicity suppression correlates with an increase in the amount of SDS-resistant Htt103Q. The specific goals of the proposed research are (1) to determine the link between aggregation and Q-rich protein mediated suppression of Htt toxicity and (2) to define the cellular pathway by which protective facilitated aggregation occurs. These goals will be achieved by means such as visual and biochemical monitoring of aggregation and genetic manipulation of yeast in epistatic experiments. Data obtained during these studies will be applied to some neuronal models for HD including a PC12 cell line which inducibly expresses a mutant Htt fragment. Altogether, these studies will define basic principles for suppression of proteotoxicity of an amyloidogenic disease protein via aggregation. This information will uncover a pathway for organized facilitated assembly of proteotoxic species and how certain cellular factors, such as Q-rich proteins and molecular chaperones, modulate assembly.

Public Health Relevance

Huntington's Disease is a highly studied, yet poorly understood neurodegenerative disorder. This project will lead to a better molecular understanding for how toxicity of mutant Huntingtin, the disease associated protein, can be modulated based on modulation of aggregation status.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F05-A (20))
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Sutherland, Margaret L
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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