Grace Le

INVESTIGATING ZIP7 ERAD ENHANCING FUNCTION TO PREVENT NEURODEGENERATION IN FLIES

Grace Le, Nishi Rauth, Denise Montell Ph.D.

The accumulation and aggregation of toxic misfolded proteins causes many degenerative diseases such as Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Retinitis pigmentosa (RP) etc. In the endoplasmic reticulum (ER), a quality control mechanism known as ER-associated degradation (ERAD) maintains protein homeostasis. ERAD targets misfolded proteins via ubiquitin to be degraded by the proteasome. A groundbreaking finding in Denise Montell's lab is that ZIP7 enhances ERAD by providing rate-limiting zinc to the proteasomal component Rpn11, a zinc-dependent deubiquitinase. ZIP7 is a conserved ER-localized zinc transporter and knock down causes ER stress. Moreover, overexpression of dZIP7 is sufficient to degrade misfolded rhodopsin, rescue ER stress and prevent retinal degeneration in a fly model of RP, a genetic disease that leads to blindness. This finding opens the possibility of implementing ZIP7 as a gene therapy to treat RP in humans. Currently, we are investigating if dZIP7 overexpression could prevent neurodegeneration in Drosophila eyes caused by myriads of human-neurotoxic proteins. Therefore, my current research focus is to perform a screen modeling neurodegeneration in the Drosophila eye using the UAS/Gal4 system. Gal4 will ectopically drives the expression of neurotoxic proteins and dZIP7 to the Drosophila eye allowing us to score for rescue of retinal degeneration. I hypothesize that dZIP7 overexpression will be able to rescue proteotoxicity induced by proteins that are degraded via ERAD. The findings from this research will elucidate whether ZIP7 gene therapy might be more broadly effective against degenerative diseases caused by protein misfolding.