| First Author | Guardia-Laguarta C | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 1 | Pages | 249-59 |
| PubMed ID | 24381286 | Mgi Jnum | J:205588 |
| Mgi Id | MGI:5545851 | Doi | 10.1523/JNEUROSCI.2507-13.2014 |
| Citation | Guardia-Laguarta C, et al. (2014) alpha-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci 34(1):249-59 |
| abstractText | Familial Parkinson disease is associated with mutations in alpha-synuclein (alpha-syn), a presynaptic protein that has been localized not only to the cytosol, but also to mitochondria. We report here that wild-type alpha-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 alpha-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 alpha-syn in mutant alpha-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 alpha-syn operates downstream of the mitochondrial fusion/fission machinery. These novel results indicate that wild-type alpha-syn localizes to the MAM and modulates mitochondrial morphology, and that these behaviors are impaired by pathogenic mutations in alpha-syn. We believe that our results have far-reaching implications for both our understanding of alpha-syn biology and the treatment of synucleinopathies. |
