α-synuclein is localized to mitochondria-associated ER membranes

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Abstract

Familial Parkinson disease is associated with mutations inα-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 humanα-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-synexpressing 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 thatα-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. © 2014 the authors.

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Guardia-Laguarta, C., Area-Gomez, E., Rüb, C., Liu, Y., Magrané, J., Becker, D., … Przedborski, S. (2014). α-synuclein is localized to mitochondria-associated ER membranes. Journal of Neuroscience, 34(1), 249–259. https://doi.org/10.1523/JNEUROSCI.2507-13.2014

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