Small molecule modulators of autophagy in neurodegenerative disorders.

Abstract : Macroautophagy(herein autophagy) is an evolutionarily conserved intracellular recycling process. Autophagy involves formation of ade novo double membrane vesicle, the autophagosome, that captures cytosolic cargoes including proteins and organelles and delivers it to the lysosome for degradation. Breakdown of the constituents of autophagosomes releases basic building blocks such as amino acids, sugars and lipids back into the cytosol which can be used to prevail nutrient deprivation conditions. Thus autophagy is a pro-survival mechanism that that also helps maintain cellular homeostasis by removing damaged and/or excess cytosolic components including protein aggregates. Dysfunctional autophagy is seen in many disorders including neurodegenerative disorders including Parkinson's disease. Thus restoring autophagy in such situations may have beneficial effects due to clearance of cellular protein aggregates. We developed a yeast based high throughput assay for screening small molecule libraries for autophagy modulators. Characterization of the "hits" identified small molecules that acted at various stages of autophagosome biogenesis. Furthermore, employing a protein aggregation yeast model, we screened small molecule library and identified several hits that were able to rescue cellular cytotoxicity in an autophagy dependent manner. We further characterized one of the hits in mammalian cell culture and mouse models of Parkinson's to highlight the importance of functional autophagy in neurodegenerative disorders.