title: α-Synuclein is localized to mitochondria-associated ER membranes.
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.
authors.affiliation: Departments of Pathology, Neurology, and Genetics and Development, and Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, Institut für Biochemie und Molekularbiologie, Universität 53115 Bonn, Germany, and Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rüb
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Liu
authors.forename: Jordi
authors.initials: J
authors.lastname: Magrané
authors.forename: Dorothea
authors.initials: D
authors.lastname: Becker
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voos
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry*; D051844:alpha-Synuclein / Q000032:analysis*
chemical_list: D051844:alpha-Synuclein