2005 New Investigator Research Grant

In almost all neurodegenerative diseases, including Alzheimer’s disease, clumps, or aggregates, of proteins can be found inside or adjacent to damaged neurons. This suggests that cellular mechanisms for removing damaged or unwanted proteins may not be functioning properly in these disorders, and indeed, there is evidence to support this contention. However, it is unclear whether this malfunction is a cause or a consequence of disease.

Heather True-Krob, Ph.D., and colleagues will address this question using yeast as a model system. Unlike human cells, yeast cells can harbor aggregates of certain proteins without suffering toxic side effects. The researchers plan to induce protein aggregation in yeast and then examine if the aggregates hamper the normal protein degradation machinery. They will also examine how a mutant protein, called ubiquitin, which has been linked to Alzheimer’s disease, can affect degradation of protein aggregates in yeast.

The mutant ubiquitin arises through a process called “molecular misreading.” This is when the genetic instructions for the protein are not faithfully decoded. Why this happens is unclear, but the scientists will investigate if protein aggregation can somehow lead to molecular misreading. The findings will lead to a better understanding of the relationship among the protein degradation machinery, protein aggregates and disease. The results may also point to strategies for new therapeutic interventions.