α-Synuclein is localized to mitochondria-associated ER membranes. Academic Article uri icon

Overview

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.

publication date

  • January 1, 2014

Research

keywords

  • Endoplasmic Reticulum
  • Mitochondria
  • alpha-Synuclein

Identity

PubMed Central ID

  • PMC3866487

Scopus Document Identifier

  • 45349089531

Digital Object Identifier (DOI)

  • 10.1074/jbc.R800011200

PubMed ID

  • 24381286

Additional Document Info

volume

  • 34

issue

  • 1