Dataset Information

Inhibition of mitochondrial fusion by ?-synuclein is rescued by PINK1, Parkin and DJ-1.

ABSTRACT: Aggregation of ?-synuclein (?S) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of ?S is largely unknown. We demonstrate with in vitro vesicle fusion experiments that ?S has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, ?S binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous ?S. In contrast, siRNA-mediated downregulation of ?S results in elongated mitochondria in cell culture. ?S can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, ?S prevents fusion of differently labelled mitochondrial populations. Thus, ?S inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of ?S is rescued by coexpression of PINK1, parkin or DJ-1 but not the PD-associated mutations PINK1 G309D and parkin ?1-79 or by DJ-1 C106A.

SUBMITTER: Kamp F

PROVIDER: S-EPMC2964170 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1.

Kamp Frits F Exner Nicole N Lutz Anne Kathrin AK Wender Nora N Hegermann Jan J Brunner Bettina B Nuscher Brigitte B Bartels Tim T Giese Armin A Beyer Klaus K Eimer Stefan S Winklhofer Konstanze F KF Haass Christian C

The EMBO journal 20100914 20

Aggregation of α-synuclein (αS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of αS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that αS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, αS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mit ...[more]

PMID: 20842103

Similar Datasets

Project description:Mitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson's disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson's disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1-120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1-120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1-120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.

Dataset Information

Inhibition of mitochondrial fusion by ?-synuclein is rescued by PINK1, Parkin and DJ-1.

Publications

Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets