Inhibition of mitochondrial fusion by α‐synuclein is rescued by PINK1, Parkin and DJ‐1
Identifieur interne : 000669 ( Main/Exploration ); précédent : 000668; suivant : 000670Inhibition of mitochondrial fusion by α‐synuclein is rescued by PINK1, Parkin and DJ‐1
Auteurs : Frits Kamp [Allemagne] ; Nicole Exner [Allemagne] ; Anne Kathrin Lutz [Allemagne] ; Nora Wender [Allemagne] ; Jan Hegermann [Allemagne] ; Bettina Brunner [Allemagne] ; Brigitte Nuscher [Allemagne] ; Tim Bartels [Allemagne] ; Armin Giese [Allemagne] ; Klaus Beyer [Allemagne, États-Unis] ; Stefan Eimer [Allemagne] ; Konstanze F. Winklhofer [Allemagne] ; Christian Haass [Allemagne]Source :
- The EMBO Journal [ 0261-4189 ] ; 2010-10-20.
Abstract
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.
Url:
DOI: 10.1038/emboj.2010.223
Affiliations:
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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.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>Bavière</li><li>District de Haute-Bavière</li></region><settlement><li>Munich</li></settlement></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Kamp, Frits" sort="Kamp, Frits" uniqKey="Kamp F" first="Frits" last="Kamp">Frits Kamp</name></region><name sortKey="Bartels, Tim" sort="Bartels, Tim" uniqKey="Bartels T" first="Tim" last="Bartels">Tim Bartels</name><name sortKey="Beyer, Klaus" sort="Beyer, Klaus" uniqKey="Beyer K" first="Klaus" last="Beyer">Klaus Beyer</name><name sortKey="Brunner, Bettina" sort="Brunner, Bettina" uniqKey="Brunner B" first="Bettina" last="Brunner">Bettina Brunner</name><name sortKey="Brunner, Bettina" sort="Brunner, Bettina" uniqKey="Brunner B" first="Bettina" last="Brunner">Bettina Brunner</name><name sortKey="Eimer, Stefan" sort="Eimer, Stefan" uniqKey="Eimer S" first="Stefan" last="Eimer">Stefan Eimer</name><name sortKey="Exner, Nicole" sort="Exner, Nicole" uniqKey="Exner N" first="Nicole" last="Exner">Nicole Exner</name><name sortKey="Exner, Nicole" sort="Exner, Nicole" uniqKey="Exner N" first="Nicole" last="Exner">Nicole Exner</name><name sortKey="Giese, Armin" sort="Giese, Armin" uniqKey="Giese A" first="Armin" last="Giese">Armin Giese</name><name sortKey="Haass, Christian" sort="Haass, Christian" uniqKey="Haass C" first="Christian" last="Haass">Christian Haass</name><name sortKey="Haass, Christian" sort="Haass, Christian" uniqKey="Haass C" first="Christian" last="Haass">Christian Haass</name><name sortKey="Hegermann, Jan" sort="Hegermann, Jan" uniqKey="Hegermann J" first="Jan" last="Hegermann">Jan Hegermann</name><name sortKey="Kamp, Frits" sort="Kamp, Frits" uniqKey="Kamp F" first="Frits" last="Kamp">Frits Kamp</name><name sortKey="Lutz, Anne Kathrin" sort="Lutz, Anne Kathrin" uniqKey="Lutz A" first="Anne Kathrin" last="Lutz">Anne Kathrin Lutz</name><name sortKey="Nuscher, Brigitte" sort="Nuscher, Brigitte" uniqKey="Nuscher B" first="Brigitte" last="Nuscher">Brigitte Nuscher</name><name sortKey="Nuscher, Brigitte" sort="Nuscher, Brigitte" uniqKey="Nuscher B" first="Brigitte" last="Nuscher">Brigitte Nuscher</name><name sortKey="Wender, Nora" sort="Wender, Nora" uniqKey="Wender N" first="Nora" last="Wender">Nora Wender</name><name sortKey="Winklhofer, Konstanze F" sort="Winklhofer, Konstanze F" uniqKey="Winklhofer K" first="Konstanze F" last="Winklhofer">Konstanze F. Winklhofer</name></country><country name="États-Unis"><noRegion><name sortKey="Beyer, Klaus" sort="Beyer, Klaus" uniqKey="Beyer K" first="Klaus" last="Beyer">Klaus Beyer</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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