α-Synuclein abnormalities in mouse models of peroxisome biogenesis disorders

Abstract

Alpha-Synuclein (aS) is a presynaptic protein implicated in Parkinson's disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress, and aS-lipid interactions in the gradual accumulation of aS in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models Pex2–/–, Pex5–/–, and Pex13–/–to study the potential effects of peroxisomal dysfunction on aS-related pathogenesis. We found increased aS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Furthermore, we show that aS abnormalities correlate with the altered lipid metabolism and, specifically, with accumulation of long chain, n-6 polyunsaturated fatty acids that occurs in the PBD models.