Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants

alpha-synuclein (alpha S) is the key component of synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. alpha S was first linked to PD through the identification of point mutations in the SNCA gene, causing single amino acid substitutions within alpha S and familial auto-somal dominant forms of PD that profoundly accelerated dis-ease onset by up to several decades. At least eight single-point mutations linked to familial PD (A30G/P, E46K, H50Q, G51D, and A53T/E/V) are located in proximity of the region preced-ing the non-beta amyloid component (preNAC) region, strongly implicating its pathogenic role in alpha S-mediated cytotoxicity. Furthermore, lipids are known to be important for native alpha S function, where they play a key role in the regulation of syn-aptic vesicle docking to presynaptic membranes and dopamine transmission. However, the role of lipids in the function of mutant alpha S is unclear. Here, we studied alpha S aggregation prop-erties of WT alpha S and five of the most predominant single-point missense mutants associated with early onset PD in the pres-ence of anionic 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine lipid vesicles. Our results highlight significant differences be-tween aggregation rates, the number of aggregates produced, and overall fibril morphologies of WT alpha S and the A30P, E46K, H50Q, G51D, and A53T missense mutants in the presence of lipid vesicles. These findings have important implications regarding the interplay between the lipids required for alpha S function and the individual point mutations known to accel-erate PD and related diseases.

Automated summary

This article investigates the role of alpha-synuclein in synucleinopathies and explores the interplay between mutant alpha-synuclein and lipids.