SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinsons disease
Identifieur interne : 000436 ( Main/Exploration ); précédent : 000435; suivant : 000437SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinsons disease
Auteurs : Pablo Garcia-Reitbck [Royaume-Uni] ; Oleg Anichtchik [Royaume-Uni] ; Arianna Bellucci [Italie] ; Mariangela Iovino [Royaume-Uni] ; Chiara Ballini [Italie] ; Elena Fineberg [Royaume-Uni] ; Bernardino Ghetti [États-Unis] ; Laura Della Corte [Italie] ; Pierfranco Spano [Italie] ; George K. Tofaris [Royaume-Uni] ; Michel Goedert [Royaume-Uni] ; Maria Grazia Spillantini [Royaume-Uni]Source :
- Brain [ 0006-8950 ] ; 2010-07.
Abstract
The pre-synaptic protein -synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinsons disease and dementia with Lewy bodies. Mutations in the -synuclein gene cause familial forms of Parkinsons disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human -synuclein(1-120) that develops -synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinsons disease. We now show that in the striatum of these mice, as in Parkinsons disease, synaptic accumulation of -synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length -synuclein(1140) or truncated -synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of -synuclein at the synapse, which may be an early event in the pathogenesis of Parkinsons disease.
Url:
DOI: 10.1093/brain/awq132
Affiliations:
- Italie, Royaume-Uni, États-Unis
- Angleterre, Angleterre de l'Est, Oxfordshire
- Cambridge, Oxford
- Université d'Oxford, Université de Cambridge
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Mutations in the -synuclein gene cause familial forms of Parkinsons disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human -synuclein(1-120) that develops -synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinsons disease. We now show that in the striatum of these mice, as in Parkinsons disease, synaptic accumulation of -synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length -synuclein(1140) or truncated -synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of -synuclein at the synapse, which may be an early event in the pathogenesis of Parkinsons disease.</div></front></TEI><affiliations><list><country><li>Italie</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li><li>Oxfordshire</li></region><settlement><li>Cambridge</li><li>Oxford</li></settlement><orgName><li>Université d'Oxford</li><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Garcia Reitbck, Pablo" sort="Garcia Reitbck, Pablo" uniqKey="Garcia Reitbck P" first="Pablo" last="Garcia-Reitbck">Pablo Garcia-Reitbck</name></region><name sortKey="Anichtchik, Oleg" sort="Anichtchik, Oleg" uniqKey="Anichtchik O" first="Oleg" last="Anichtchik">Oleg Anichtchik</name><name sortKey="Fineberg, Elena" sort="Fineberg, Elena" uniqKey="Fineberg E" first="Elena" last="Fineberg">Elena Fineberg</name><name sortKey="Goedert, Michel" sort="Goedert, Michel" uniqKey="Goedert M" first="Michel" last="Goedert">Michel Goedert</name><name sortKey="Iovino, Mariangela" sort="Iovino, Mariangela" uniqKey="Iovino M" first="Mariangela" last="Iovino">Mariangela Iovino</name><name sortKey="Spillantini, Maria Grazia" sort="Spillantini, Maria Grazia" uniqKey="Spillantini M" first="Maria Grazia" last="Spillantini">Maria Grazia Spillantini</name><name sortKey="Spillantini, Maria Grazia" sort="Spillantini, Maria Grazia" uniqKey="Spillantini M" first="Maria Grazia" last="Spillantini">Maria Grazia Spillantini</name><name sortKey="Tofaris, George K" sort="Tofaris, George K" uniqKey="Tofaris G" first="George K." last="Tofaris">George K. Tofaris</name></country><country name="Italie"><noRegion><name sortKey="Bellucci, Arianna" sort="Bellucci, Arianna" uniqKey="Bellucci A" first="Arianna" last="Bellucci">Arianna Bellucci</name></noRegion><name sortKey="Ballini, Chiara" sort="Ballini, Chiara" uniqKey="Ballini C" first="Chiara" last="Ballini">Chiara Ballini</name><name sortKey="Della Corte, Laura" sort="Della Corte, Laura" uniqKey="Della Corte L" first="Laura" last="Della Corte">Laura Della Corte</name><name sortKey="Spano, Pierfranco" sort="Spano, Pierfranco" uniqKey="Spano P" first="Pierfranco" last="Spano">Pierfranco Spano</name></country><country name="États-Unis"><noRegion><name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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