Article

Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein

Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 06/2011; 286(23):20710-26. DOI: 10.1074/jbc.M110.213538
Source: PubMed

ABSTRACT The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.

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    • "Moreover , αsyn can translocate to mitochondria and accumulate, causing complex I impairment [61] [63]. Our results, showing mitochondrial fragmentation, are in agreement with the literature [26] [43] [44] [62] [64], excluding Zhu et al. (2012) [45]. Moreover, our data suggest that there is a relationship between the presence of αsyn oligomers in the cytoplasm and variations in mitochondria morphology, while others could only establish a link between αsyn overexpression and mitochondria conditions. "
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    • "The knockout of alpha‐synuclein, pink1, parkin and DJ‐1 in drosophila and cell culture based models leads to alterations in mitochondrial morphology and network formation (Clark et al. 2006; Greene et al. 2003; Martin et al. 2006; Nakamura et al. 2011; Park et al. 2005; Park et al. 2009). Mutations in alpha‐synuclein have been shown to cause fragmentation of the mitochondrial network and changes in the ultrastructure and distribution of the mitochondria suggesting increased mitochondrial fission, (Nakamura et al. 2011). Mutations in Pink1 and Parkin have been shown to cause a loss of mitochondrial ultrastructure as observed as changes in the electron density of the mitochondria and fragmentation of the mitochondrial network (Clark et al. 2006; Greene et al. 2003). "
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    • "As shown in Fig. 6B, a dramatic increase of 255% (normalized by the total homogenate protein content) in GSSG/GSH ratio was found in NH 2 htau-infected cultures in contrast to control ones, further suggesting that their mitochondria were largely defective being source of deleterious ROS. Consistently with obvious ultrastructural changes (Fig. 1A) and in a similar way of other pathogenetic proteins that are also localized to mitochondria in different neurodegenerative human diseases, such as Parkinson's Disease (PD)-associated A53Tα-synuclein (Choubey et al., 2011; Nakamura et al., 2011) and DJ1 (Wang et al., 2012) and ALSlinked mutant SODG93A (Magrané et al., 2012), these results demonstrate that the NH 2 htau fragment impinges on the mitochondrial oxidative capacity and the antioxidant defense in neurons also by affecting the quality control of mitochondria. "
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