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

Autor: Nora Wender, Tim Bartels, Jan Hegermann, Konstanze F. Winklhofer, Christian Haass, Bettina Brunner, Frits Kamp, Anne Kathrin Lutz, Nicole Exner, Brigitte Nuscher, Armin Giese, Stefan Eimer, Klaus Beyer
Rok vydání: 2010
Předmět:
animal diseases
Protein Deglycase DJ-1
parkin protein
Mitochondrion
Membrane Fusion
Parkin
ultrastructure [Mitochondria]
metabolism [alpha-Synuclein]
metabolism [Protein Kinases]
metabolism [Oncogene Proteins]
genetics [Ubiquitin-Protein Ligases]
Oncogene Proteins
Cell fusion
General Neuroscience
genetics [Protein Kinases]
Neurodegeneration
Intracellular Signaling Peptides and Proteins
Parkinson Disease
metabolism [Caenorhabditis elegans]
Immunohistochemistry
Mitochondria
Cell biology
mitochondrial fusion
PARK7 protein
human
genetics [alpha-Synuclein]
alpha-Synuclein
genetics [Caenorhabditis elegans]
PTEN-induced putative kinase
metabolism [Intracellular Signaling Peptides and Proteins]
Vesicle fusion
Ubiquitin-Protein Ligases
metabolism [Parkinson Disease]
PINK1
Biology
Article
General Biochemistry
Genetics and Molecular Biology
Cell Line
cytology [Caenorhabditis elegans]
metabolism [Ubiquitin-Protein Ligases]
ddc:570
medicine
Animals
Humans
Caenorhabditis elegans
Molecular Biology
General Immunology and Microbiology
Lipid bilayer fusion
genetics [Oncogene Proteins]
metabolism [Mitochondria]
medicine.disease
pathology [Parkinson Disease]
nervous system diseases
nervous system
genetics [Intracellular Signaling Peptides and Proteins]
physiology [Membrane Fusion]
Protein Kinases
Zdroj: The EMBO journal 29(20), 3571-3589 (2010). doi:10.1038/emboj.2010.223
ISSN: 1460-2075
0261-4189
DOI: 10.1038/emboj.2010.223
Popis: 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 mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous αS. In contrast, siRNA-mediated downregulation of αS results in elongated mitochondria in cell culture. αS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, αS prevents fusion of differently labelled mitochondrial populations. Thus, αS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of αS is rescued by coexpression of PINK1, parkin or DJ-1 but not the PD-associated mutations PINK1 G309D and parkin Δ1-79 or by DJ-1 C106A.
Databáze: OpenAIRE
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