The molecular and metabolic mechanisms that go awry during the course of neurodegeneration remain poorly understood. A conserved protein called ataxin-2 has been linked to neurodegeneration due to the occurrence of polyglutamine tract expansions that can influence the aggregation of itself and other proteins. However, the normal functions of this protein and the consequences of their alteration have not been clear. It was recently shown that the protein can function as a redox sensor to then regulate cellular metabolism and signaling in a manner that sustains mitochondrial health and cell survivability. This proposal will investigate aspects of the mechanism of redox sensing by ataxin-2 in both yeast and mammalian cells, the downstream outputs, as well as the consequences of mutations and variants on associated cellular functions.
We plan to investigate a conserved protein involved in sensing the redox and metabolic state of cells and neurons. Mutations in this protein have been linked to mitochondrial dysfunction and neurodegenerative disease. We hope these studies will provide key insights into the mechanisms leading to neurodegeneration and reveal innovative therapeutic strategies for the treatment of such conditions.