The differential effect of lipid upon aggregation of early-onset associated α-synuclein missense mutants

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α-synuclein (αS) is the key component of synucleinopathies that include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). αS was first linked to PD through the identification of point mutations in the SNCA gene, causing single amino acid substitutions within αS and familial autosomal dominant forms of PD that profoundly accelerate disease onset by up to several decades. At least eight single-point mutations linked to familial Parkinson’s disease (A30G/P, E46K, H50Q, G51D, A53T/E/V) are located in proximity of the preNAC region, strongly implicating its pathogenic role in αS-mediated cytotoxicity. Here αS aggregation properties are studied in the presence of DMPS lipid vesicles for wild-type αS and five of the most predominant single point missense mutants associated with early onset PD. Lipids are known to be important for native αS function, where they play a key role in the regulation of synaptic vesicle docking to presynaptic membranes, and dopamine transmission. Experiments presented here highlight significant differences between aggregation rates, the number of aggregates produced, and overall fibril morphologies of wild-type αS, and the missense mutations A30P, E46K, H50Q, G51D and A53T, in the presence of lipid vesicles. These findings have important implications regarding the interplay between the lipids required for αS function and the individual point mutations known to accelerate PD and related diseases.
Original languageEnglish
Article number102565
JournalJournal of Biological Chemistry
Early online date5 Oct 2022
Publication statusE-pub ahead of print - 5 Oct 2022


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