Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys.
Identifieur interne : 000607 ( Hal/Curation ); précédent : 000606; suivant : 000608Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys.
Auteurs : Ariadna Recasens [Espagne] ; Benjamin Dehay [France] ; Jordi Bové [Espagne] ; Iria Carballo-Carbajal [Espagne] ; Sandra Dovero [France] ; Ana P Erez-Villalba [Espagne] ; Pierre Olivier Fernagut [France] ; Javier Blesa [Espagne] ; Annabelle Parent [Espagne] ; Celine Perier [Espagne] ; Isabel Fari As [Espagne] ; José Obeso [Espagne] ; Erwan Bezard [France] ; Miquel Vila [Espagne]Source :
- Annals of Neurology [ 0364-5134 ] ; 2013-11-16.
Abstract
OBJECTIVE: Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. METHODS: Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. RESULTS: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. INTERPRETATION: α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.
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DOI: 10.1002/ana.24066
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<author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name>
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<author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name>
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<idno type="DOI">10.1002/ana.24066</idno>
<series><title level="j">Annals of Neurology</title>
<idno type="ISSN">0364-5134</idno>
<imprint><date type="datePub">2013-11-16</date>
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<front><div type="abstract" xml:lang="en">OBJECTIVE: Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. METHODS: Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. RESULTS: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. INTERPRETATION: α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.</div>
</front>
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<hal api="V3"> <titleStmt> <title xml:lang="en">Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys.</title>
<author role="aut"> <persName> <forename type="first">Ariadna</forename>
<surname>Recasens</surname>
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<idno type="halauthorid">1053462</idno>
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<author role="aut"> <persName> <forename type="first">Benjamin</forename>
<surname>Dehay</surname>
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<author role="aut"> <persName> <forename type="first">Jordi</forename>
<surname>Bové</surname>
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<surname>Carballo-Carbajal</surname>
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<author role="aut"> <persName> <forename type="first">Sandra</forename>
<surname>Dovero</surname>
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<author role="aut"> <persName> <forename type="first">Ana</forename>
<surname>P Erez-Villalba</surname>
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</author>
<author role="aut"> <persName> <forename type="first">Pierre Olivier</forename>
<surname>Fernagut</surname>
</persName>
<idno type="halauthorid">430549</idno>
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<author role="aut"> <persName> <forename type="first">Javier</forename>
<surname>Blesa</surname>
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<idno type="halauthorid">1053466</idno>
<affiliation ref="#struct-260889"></affiliation>
</author>
<author role="aut"> <persName> <forename type="first">Annabelle</forename>
<surname>Parent</surname>
</persName>
<idno type="halauthorid">1053467</idno>
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<author role="aut"> <persName> <forename type="first">Celine</forename>
<surname>Perier</surname>
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<idno type="halauthorid">1053468</idno>
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</author>
<author role="aut"> <persName> <forename type="first">Isabel</forename>
<surname>Fariñas</surname>
</persName>
<idno type="halauthorid">1053469</idno>
<affiliation ref="#struct-260888"></affiliation>
</author>
<author role="aut"> <persName> <forename type="first">José</forename>
<forename type="middle">A.</forename>
<surname>Obeso</surname>
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<idno type="halauthorid">537315</idno>
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<author role="crp"> <persName> <forename type="first">Erwan</forename>
<surname>Bezard</surname>
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<email type="md5">b0deb6c343e8d1ae022cfd4a58cecc43</email>
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<author role="crp"> <persName> <forename type="first">Miquel</forename>
<surname>Vila</surname>
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<email type="domain">ir.vhebron.net</email>
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<editor role="depositor"> <persName> <forename>Catherine</forename>
<surname>Griveau</surname>
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<email type="md5">2721a25e4c55ec4e1a64e00a1898f5bc</email>
<email type="domain">u-bordeaux.fr</email>
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<date type="whenModified">2016-03-10 10:43:42</date>
<date type="whenReleased">2015-12-22 14:49:03</date>
<date type="whenProduced">2013-11-16</date>
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<name key="194354"> <persName> <forename>Catherine</forename>
<surname>Griveau</surname>
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<email type="domain">u-bordeaux.fr</email>
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<idno type="halId">hal-01022197</idno>
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<idno type="halRefHtml">Annals of Neurology, Wiley, 2013, 75 (3), pp.351-362. <10.1002/ana.24066></idno>
<idno type="halRef">Annals of Neurology, Wiley, 2013, 75 (3), pp.351-362. <10.1002/ana.24066></idno>
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<note type="peer" n="1">Yes</note>
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<sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys.</title>
<author role="aut"> <persName> <forename type="first">Ariadna</forename>
<surname>Recasens</surname>
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<idno type="halauthorid">1053462</idno>
<affiliation ref="#struct-260885"></affiliation>
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<author role="aut"> <persName> <forename type="first">Benjamin</forename>
<surname>Dehay</surname>
</persName>
<idno type="halauthorid">159357</idno>
<affiliation ref="#struct-244085"></affiliation>
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<author role="aut"> <persName> <forename type="first">Jordi</forename>
<surname>Bové</surname>
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<idno type="halauthorid">1053463</idno>
<affiliation ref="#struct-260886"></affiliation>
</author>
<author role="aut"> <persName> <forename type="first">Iria</forename>
<surname>Carballo-Carbajal</surname>
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<author role="aut"> <persName> <forename type="first">Sandra</forename>
<surname>Dovero</surname>
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<idno type="halauthorid">646731</idno>
<affiliation ref="#struct-244085"></affiliation>
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<author role="aut"> <persName> <forename type="first">Ana</forename>
<surname>P Erez-Villalba</surname>
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<idno type="halauthorid">1053465</idno>
<affiliation ref="#struct-260888"></affiliation>
</author>
<author role="aut"> <persName> <forename type="first">Pierre Olivier</forename>
<surname>Fernagut</surname>
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<idno type="halauthorid">430549</idno>
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<author role="aut"> <persName> <forename type="first">Javier</forename>
<surname>Blesa</surname>
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<author role="aut"> <persName> <forename type="first">Annabelle</forename>
<surname>Parent</surname>
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<author role="aut"> <persName> <forename type="first">Celine</forename>
<surname>Perier</surname>
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<author role="aut"> <persName> <forename type="first">Isabel</forename>
<surname>Fariñas</surname>
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<author role="aut"> <persName> <forename type="first">José</forename>
<forename type="middle">A.</forename>
<surname>Obeso</surname>
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<author role="crp"> <persName> <forename type="first">Erwan</forename>
<surname>Bezard</surname>
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<email type="domain">u-bordeaux2.fr</email>
<idno type="halauthorid">506531</idno>
<affiliation ref="#struct-244085"></affiliation>
</author>
<author role="crp"> <persName> <forename type="first">Miquel</forename>
<surname>Vila</surname>
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<email type="md5">d30bc1a110d1d0799bc599e8dde2c09f</email>
<email type="domain">ir.vhebron.net</email>
<idno type="halauthorid">1053470</idno>
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</analytic>
<monogr> <idno type="halJournalId" status="VALID">10490</idno>
<idno type="issn">0364-5134</idno>
<idno type="eissn">1531-8249</idno>
<title level="j">Annals of Neurology</title>
<imprint> <publisher>Wiley</publisher>
<biblScope unit="volume">75</biblScope>
<biblScope unit="issue">3</biblScope>
<biblScope unit="pp">351-362</biblScope>
<date type="datePub">2013-11-16</date>
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<idno type="doi">10.1002/ana.24066</idno>
<idno type="pubmed">24243558</idno>
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<profileDesc> <langUsage> <language ident="en">English</language>
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<abstract xml:lang="en">OBJECTIVE: Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. METHODS: Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. RESULTS: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. INTERPRETATION: α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.</abstract>
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