Autophagy modulates Aß accumulation and formation of aggregates in yeast.

Intracellular accumulation of amyloid-ß protein (Aß) is an early event in Alzheimer's disease (AD). The autophagy-lysosomal pathway is an important pathway for maintaining cellular proteostasis and for the removal of damaged organelles and protein aggregates in all eukaryotes. Despite mounting evidence showing that modulating autophagy promotes clearance of Aß aggregates, the regulatory mechanisms and signalling pathways underlying this process remain poorly understood. In order to gain better insight we used our previously characterised yeast model expressing GFP-Aß42 to identify genes that regulate the removal of Aß42 aggregates by autophagy. We report that GFP-Aß42 is sequestered and is selectively transported to vacuole for degradation and that autophagy is the prominent pathway for clearance of aggregates. Next, to identify genes that selectively promote the removal of Aß42 aggregates, we screened levels of GFP-Aß42 and non-aggregating GFP-Aß42 (19:34) proteins in a panel of 192 autophagy mutants lacking genes involved in regulation and initiation of the pathway, cargo selection and degradation processes. The nutrient and stress signalling genes RRD1, SNF4, GCN4 and SSE1 were identified. Deletion of these genes impaired GFP-Aß42 clearance and their overexpression reduced GFP-Aß42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aß42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.