Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1.
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.
Kamp
Frits
F
DZNE-German Center for Neurodegenerative Diseases,Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Munich, Germany. fkamp@med.uni-muenchen.de
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
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C105131:PARK7 protein, human