Alpha-Synuclein and Lipids: The Elephant in the Room?

Abstract

Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

Lactobacillus plantarum DP189 Reduces α-SYN Aggravation in MPTP-Induced Parkinson’s Disease Mice via Regulating Oxidative Damage, Inflammation, and Gut Microbiota Disorder

“…23 Growing studies had shown that the accumulation of α-SYN in the SN accelerated the apoptosis of dopaminergic neurons and eventually led to PD. 24 We found that the intervention with L. plantarum DP189 reduced the accumulation of α-SYN, which also revealed that L. plantarum DP189 could resist the development of PD. Of note, the accumulation of α-SYN seems to be positively correlated with the oxidation level of the body.…”

“…As a key protein in the development of PD, α-SYN plays an important role in the production of PD . Growing studies had shown that the accumulation of α-SYN in the SN accelerated the apoptosis of dopaminergic neurons and eventually led to PD . We found that the intervention with L.…”

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

“…Because of the high curvature and increased phospholipid packing defects, αS preferentially binds to SUVs (∼40 nm diameter). These are comparable in size to vesicles found at the synaptic terminal of dopaminergic neurons, relative to large unilamellar vesicles (>100 nm) ( 41 , 42 , 43 ). Moreover, αS binding to lipid vesicles can act as an anchor point for aggregation, accelerating primary nucleation, and this is particularly the case at lower lipid:protein ratios because of the sufficiently high concentration of monomeric αS remaining in solution to contribute to fibril growth ( 27 , 32 , 38 ).…”

Lipidomics of Bioactive Lipids in Alzheimer’s and Parkinson’s Diseases: Where Are We?

“…Although the etiology of PD is generally unknown, the formation of α-syn aggregates seems to be closely associated to an altered lipid metabolism. Indeed, despite the fact that the physiological role of α-syn is yet not fully understood, it appears that its accumulation and aggregation are either enhanced by membrane lipid composition or they further cause alterations in lipid homeostasis [ 88 ]. Furthermore, genome-wide screening studies in yeast support the involvement of lipid metabolism in α-syn toxicity, with many genes associated with lipid metabolism, modifying toxicity, and vesicle-mediated transport [ 89 ].…”