This R03 application is in response to NIA PAR-03-056 Research Objective #7 Protein Modification, Aggregation and Degradation in Aging and Age-Related Diseases and also has some relevance to Research Objective # 4 Transmissible Spongiform Encephalopathies. The objective of this pilot project is to develop a model system to study the mechanism of protein misfolding and heterotypic protein aggregation. Co-aggregation of misfolded proteins represents a plausible hypothesis for the inexplicably high sporadic nature of several neurodegenerative disorders. One misfolded protein may serve as a template or seed on which other proteins aggregate. Alternatively, there may be a titration of an inhibitor or chaperone with the existence of the initial aggregate that allows for additional aggregates to form. A third possibility is that there may be a broader change in cellular physiology with the appearance of one aggregate that allows for known disease-associated proteins such as huntingtin, Abeta, and alpha-synuclein to aggregate. To complicate matters, none of these hypotheses need to be mutually exclusive. We are developing a model system to test these possibilities in the development of co-aggregation. This model system is based on yeast prion proteins that will allow us to understand the mechanism and regulation of heterotypic co-aggregation in vivo. There are striking similarities between the conformational change that occurs with prion proteins and those associated with misfolded proteins involved in diseases such as Huntington's, Parkinson's and Alzheimer's. Two yeast prions that are known to associate, [PSI+] and [RNQ+], will be used in this model system of protein aggregation in vivo. Assays are already in place to follow the [PSI+] prion. The specific challenge of this pilot project is to understand the biological function of both the [RNQ+] prion and its gene product, Rnq1p. Understanding the biological consequences of [RNQ+] will not only allow us to follow this twoprion system carefully, but will also lead to a greater appreciation of how broadly these prion-based epigenetic elements may influence fitness and survival.
| Strawn, Lisa A; True, Heather L (2006) Deletion of RNQ1 gene reveals novel functional relationship between divergently transcribed Bik1p/CLIP-170 and Sfi1p in spindle pole body separation. Curr Genet 50:347-66 |
