Grant: CIHR Fellowship

Neurodegenerative disease (ND) poses a major health problem in developed (and increasingly developing) countries. The most prevalent age-related NDs share a molecular link in the propensity for specific proteins to misfold and form aggregates in the brain. Moreover, systematic deletion and overexpression screens in many organisms have identified a number of genes that can modulate the toxicity associated with ND protein aggregation. However, naturally occurring genetic variants - the genetic changes that really matter to ND patients - typically do not exist as precise deletion and overexpression constructs employed in genetic screens. As such, it is pertinent to identify the natural genetic variation that can modify the toxicity caused by ND-associated proteins. Our preliminary study has demonstrated that closely-related wild yeast isolates show varying degrees of resistance to this toxicity. By comparing the sequenced genomes and employing an approach we have recently pioneered to identify causal mutations at unprecedented resolution, I can uncover potential drug targets and biomarkers for various NDs. To investigate the interplay between aging and genetic susceptibility to ND, I will take advantage of a genetically-engineered yeast strain that allows for the enrichment of cells of different ages, and examine the effect of these candidate mutations in young and aged cells. Lastly, I will validate our findings in the African turquoise killifish Nothobranchius furzeri, a genetically tractable, short-lived model for studying vertebrate aging. I will assess the age-dependent effects of the candidate mutations on ND-associated protein aggregation and behavior changes in killifish over the course of its lifespan. This work is poised to shed light on the genetic basis of NDs in the context of aging, and uncover candidate mutations that are important for the detection and treatment of the most common NDs.