Impact of several PD‐associated genes on the toxicity of a‐synuclein in a yeast model

Abstract

Parkinson's disease (PD) is characterized by a‐synuclein misfolding and the death of midbrain neurons. PD can be described as familial, or sporadic, both of which are influenced by a multitude of environmental and genetic factors. Familial PD is directly caused by a mutation in one of at least ten genes, including SNCA, DJ‐1, VPS35, and ATP13A2. SNCA, which encodes a‐synuclein, has six identified missense mutations (A30P, E46K, H50Q, G51D, A53E, and A53T) that each cause autosomal dominant PD. Sporadic PD is linked with several risk genes and loci, including VPS13, the Sac I domain of SYNJ1, and the Swa2 domain of DNAJC6. Using our previously established budding yeast model system for α‐synuclein, we first show that wild‐type (WT), E46K, A53T, H50Q, and A53E a‐synuclein are toxic to yeast and show varying degrees of membrane binding and aggregation, while A30P and G51D a‐synuclein are relatively non‐toxic and shows cytoplasmic diffuse localization. What is still not well understood is whether the other PD‐causing and risk genes mentioned above can influence toxicity and localization properties of WT a‐synuclein and these six familial PD mutants. To test the hypothesis that they do influence a‐synuclein, WT and familial mutant forms of a‐synuclein were studied in haploid yeast strains that were singly deleted for these six PD‐linked genes (all of which are linked to loss‐of‐function in PD). Results show that some gene deletions increase (Δhsp31) or decrease (Δatp13, Δvps35) a‐synuclein toxicity and alter its localization in a highly familial mutant specific way, while others more broadly increase a‐synuclein toxicity or aggregation (Δvps13, Δsac1), while still others no effect (Δswa2). Our findings suggest that WT and each familial mutant of a‐synuclein create cellular toxicity and alter localization in distinct ways and that each is likely regulated by different subsets of genes, opening doors for mutant‐specific mechanistic insight into the varying modes of a‐synuclein toxicity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.