976C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Kevin Hope; Alexys Berman; Clement Chow

Affiliation: Human Genetics, University of Utah, Salt Lake City, UT

Keywords:
u. drug discovery; g. unfolded protein response

Misfolded protein accumulation in the endoplasmic reticulum (ER) induces ER stress. Cells respond to ER stress by initiating the unfolded protein response (UPR) that upregulates chaperone protein expression, increases the degradation of misfolded proteins, and inhibits protein translation. Failure to effectively manage ER stress and restore homeostasis results in cellular dysfunction and ultimately apoptosis, a process implicated in numerous human diseases such as retinal degeneration, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Identifying small molecules that modulate ER stress may be effective therapeutics for human diseases caused by misfolded protein accumulation. Here, we used a Drosophila model of retinitis pigmentosa (RP) that expresses misfolded rhodopsin protein, Rh1^G69D, in the developing eye. Rh1^G69D expression induces chronic ER stress and apoptosis, resulting in a degenerative eye phenotype. We took a drug repurposing approach and used the Prestwick Chemical Library, consisting of 1520 small molecules, the majority of which are FDA-approved, to identify compounds that modulate neuron cell death in Rh1^G69D expressing flies. We identified multiple classes of drugs that enhance or suppress the degenerative eye phenotype, including compounds acting through monoamine neurotransmitters, folate metabolism, sodium channels, and the renin/angiotensin pathway. Degeneration-enhancing compounds may reveal novel ER stress pathways, and compounds that suppress degeneration are potential therapeutic candidates for RP. We are using an RNAi approach to identify the mechanism of action for the top enhancers and suppressors. Additionally, we will present findings on whether compounds that rescue cell death in the RP model can also rescue disease-associated phenotypes in other Drosophila models of protein misfolding diseases, such as PD, HD, and ALS. This work identified potential therapeutic drugs for RP and possibly other human diseases that result from misfolded protein accumulation and ER stress.