α-Synuclein Is Localized to Mitochondria-Associated ER Membranes

TLDR

Familial Parkinson disease is linked to mutations in α‑synuclein, a presynaptic protein found in the cytosol and mitochondria. Wild‑type α‑synuclein localizes to mitochondria‑associated ER membranes, where pathogenic mutations diminish its association, impair ER‑mitochondria apposition and MAM function, and promote mitochondrial fragmentation—a phenotype rescued by wild‑type α‑syn overexpression but not by manipulating fusion/fission proteins, underscoring α‑syn’s downstream role in mitochondrial morphology and its relevance to synucleinopathies.

Abstract

Familial Parkinson disease is associated with mutations in α-synuclein (α-syn), a presynaptic protein that has been localized not only to the cytosol, but also to mitochondria. We report here that wild-type α-syn from cell lines, and brain tissue from humans and mice, is present not in mitochondria but rather in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a structurally and functionally distinct subdomain of the ER. Remarkably, we found that pathogenic point mutations in human α-syn result in its reduced association with MAM, coincident with a lower degree of apposition of ER with mitochondria, a decrease in MAM function, and an increase in mitochondrial fragmentation compared with wild-type. Although overexpression of wild-type α-syn in mutant α-syn-expressing cells reverted the fragmentation phenotype, neither overexpression of the mitochondrial fusion/MAM-tethering protein MFN2 nor inhibition/ablation of the mitochondrial fission protein DRP1 was able to do so, implying that α-syn operates downstream of the mitochondrial fusion/fission machinery. These novel results indicate that wild-type α-syn localizes to the MAM and modulates mitochondrial morphology, and that these behaviors are impaired by pathogenic mutations in α-syn. We believe that our results have far-reaching implications for both our understanding of α-syn biology and the treatment of synucleinopathies.