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α-Synuclein Is Localized to Mitochondria-Associated ER Membranes

Guardia-Laguarta, Cristina, Area-Gomez, Estela, Rüb, Cornelia, Liu, Yuhui, Magrané, Jordi, Becker, Dorothea, Voos, Wolfgang, Schon, Eric A., Przedborski, Serge·2014·The Journal of Neuroscience
DOI 10.1523/jneurosci.2507-13.2014
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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.

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Metadata

Authors
Guardia-Laguarta, C., Area-Gomez, E., Rüb, C., Liu, Y., Magrané, J., Becker, D., Voos, W., Schon, E. A., & Przedborski, S.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2013-12-31
Volume
34
Issue
1
Pages
249-259
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.2507-13.2014
Cited by
515
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)

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