Protein aggregation and the ubiquitin/proteasome system are important players in Alzheimer's disease(AD). Protein aggregates found in AD patients often includes proteins other than those explicit in thedisease, such as a mutant ubiquitin protein (mUB). Since protein aggregation itself can impair theproteasome and, conversely, proteasomal impairment can cause protein aggregation, it is difficult todetermine the cause of the disease. Cellular toxicity associatedwith the disease makes it challenging toseparate the cause from the downstream consequence. We have developed a system, utilizing non-toxicaggregates in yeast, to determine the causal relationship of these processes. Using a tractable geneticsystem, we have characterized the effects of mUB associated with AD. Preliminary results suggest thatmUB is a natural inhibitor of the proteasome and has a tremendous enhancing effect on proteinaggregation. This unique system enables us to uncover novel factors involved in the proteasomeimpairment and protein aggregation. These discoveries will aid in the development of therapeutics for ADand other neurodegenerative disorders.
| Tank, Elizabeth M H; True, Heather L (2009) Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates. PLoS Genet 5:e1000382 |
| Tank, Elizabeth M H; Harris, David A; Desai, Amar A et al. (2007) Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability. Mol Cell Biol 27:5445-55 |
