Altered interaction between alpha-synuclein and lipid modulates inclusion body formation

Abstract

Alpha-Synuclein (αS) is strongly implicated in Parkinson’s disease (PD), characterized by the abnormal αS accumulation of cytoplasmic inclusions termed Lewy body (LB). Physiologically, αS exist predominantly as an unfolded monomer but forms α-helical structure upon lipid binding. The N-terminus segment of αS influence α-helical conformation and is essential for membrane binding. Growing evidence indicates that αS variants with enhanced membrane association are more prone to LB formation. The N-terminal segment of αS is known to influence membrane binding and concomitant structural rearrangement to adopt α-helical conformation. Using yeast model, αS with altered N-terminal sequences were analysed. Interestingly, truncating the first 8 N-terminal amino acid residues abolished αS lipid binding propensity and relieved associated αS toxicity. Conversely, αS with mutations that may enhance electrostatic interactions between amphipathic helices of αS and lipid membrane slightly increased inclusion formation and toxicity in yeast cells, indicating the toxic function of αS-lipid interaction. Additionally, αS expressed in phospholipid biosynthesis mutant cells showed increased αS aggregates around endoplasmic reticulum (ER) indicating that alterations in lipid composition can be a factor contributing to αS pathology. Understanding the initiation and progression of αS lipid binding as well as effects of altered lipid composition on αS homeostasis allow us to elucidate mechanisms underlying the PD disease onset and progression.