Autophagy modulates Aβ accumulation and formation of aggregates in yeast
Document Type
Journal Article
Publication Title
Molecular and Cellular Neuroscience
Publisher
Elsevier
School
Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences
RAS ID
31905
Funders
National Health and Medical Research Council
Grant Number
NHMRC Number : 1107109
Abstract
Intracellular accumulation of amyloid-β protein (Aβ) 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 Aβ 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-Aβ42 to identify genes that regulate the removal of Aβ42 aggregates by autophagy. We report that GFP-Aβ42 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 Aβ42 aggregates, we screened levels of GFP-Aβ42 and non-aggregating GFP-Aβ42 (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-Aβ42 clearance and their overexpression reduced GFP-Aβ42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aβ42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.
DOI
10.1016/j.mcn.2020.103466
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Comments
Bharadwaj, P. R., & Martins, R. N. (2020). Autophagy modulates Aβ accumulation and formation of aggregates in yeast. Molecular and Cellular Neuroscience, 104, Article 103466. https://doi.org/10.1016/j.mcn.2020.103466