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The intrinsically disordered protein α-synuclein (aSN) forms insoluble aggregates in the brains of Parkinson's disease (PD) patients. Cytotoxicity is attributed to a soluble aSN oligomeric species that permeabilizes membranes significantly more than monomers and fibrils. In humans, the A53T mutation induces early onset PD and increases the level of aSN oligomerization and fibrillation propensity, but Thr53 occurs naturally in aSNs of most animals. We compared aSNs from elephant, bowhead whale, and pig with human aSN. While all three animal aSNs showed significantly weakened fibrillation, elephant aSN formed much more oligomer, and pig aSN much less, than human aSN did. However, all animal aSN oligomers showed weakened permeabilization toward anionic lipid vesicles, indicative of decreased cytotoxicity. These animal aSNs share three substitutions compared to human aSN: A53T, G68E, and V95G. We analyzed aggregation and membrane binding of all eight mutants combining these three mutations. While the G68E mutation is particularly important in weakening fibrillation and possible toxicity, the strongest effect is seen when all three mutations are present. Thus, a small number of mutations can significantly decrease aSN toxicity.