Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in alpha-synuclein transgenic mice.
Identifieur interne : 000785 ( Hal/Curation ); précédent : 000784; suivant : 000786Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in alpha-synuclein transgenic mice.
Auteurs : Margot Fournier [Suisse] ; Amandine Roux [France] ; Jérôme Garrigue [France] ; Marie-Paule Muriel [France] ; Paul Blanche [France] ; Hilal Lashuel [Suisse] ; John Anderson [États-Unis] ; Robin Barbour [États-Unis] ; Jiping Huang [États-Unis] ; Sophie Tezenas Du Montcel [France] ; Alexis Brice [France] ; Olga Corti [France]Source :
- BMC Neuroscience [ 1471-2202 ] ; 2013-11-05.
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Abstract
BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), alpha-synuclein (alpha-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against alpha-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human alpha-syn (hA30Palpha-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to alpha-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar alpha-syn species phosphorylated at S129 (PS129alpha-syn) were the predominant neuropathological feature in hA30Palpha-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and alpha-syn truncated at D135 (alpha-synD135), indicating that PS129alpha-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in alpha-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of alpha-syn deposits in end-stage disease.
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DOI: 10.1186/1471-2202-14-135
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<author><name sortKey="Lashuel, Hilal" sort="Lashuel, Hilal" uniqKey="Lashuel H" first="Hilal" last="Lashuel">Hilal Lashuel</name>
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<author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name>
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<author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name>
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<idno type="DOI">10.1186/1471-2202-14-135</idno>
<series><title level="j">BMC Neuroscience</title>
<idno type="ISSN">1471-2202</idno>
<imprint><date type="datePub">2013-11-05</date>
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<profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>Parkinson's disease</term>
<term>Posttranslational modifications</term>
<term>Transgenic mice overproducing α-syn</term>
<term>Ubiquitin</term>
<term>parkin knockout mice</term>
<term>α-syn phosphorylation</term>
<term>α-syn truncation</term>
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<front><div type="abstract" xml:lang="en">BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), alpha-synuclein (alpha-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against alpha-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human alpha-syn (hA30Palpha-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to alpha-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar alpha-syn species phosphorylated at S129 (PS129alpha-syn) were the predominant neuropathological feature in hA30Palpha-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and alpha-syn truncated at D135 (alpha-synD135), indicating that PS129alpha-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in alpha-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of alpha-syn deposits in end-stage disease.</div>
</front>
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<hal api="V3"> <titleStmt> <title xml:lang="en">Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in alpha-synuclein transgenic mice.</title>
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<author role="aut"> <persName> <forename type="first">Amandine</forename>
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<author role="aut"> <persName> <forename type="first">Jérôme</forename>
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<author role="aut"> <persName> <forename type="first">Jiping</forename>
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<author role="aut"> <persName> <forename type="first">Sophie</forename>
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<surname>Brice</surname>
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<author role="crp"> <persName> <forename type="first">Olga</forename>
<surname>Corti</surname>
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<funder>Institut National de la Santé et de la Recherche Médicale, Fédération pour la Recherche sur le Cerveau, Fondation de France, Fondation ICM, APOPIS (an integrated project funded by the EU under the Sixth Framework Programme; Priority: Life Science for Health, contract no. LSHM-CT-2003-503330). MF and AR were supported by the French Ministry of Research. MF was also supported by the Fondation pour la Recherche Médicale, and AR by the Association France Parkinson.</funder>
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<sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in alpha-synuclein transgenic mice.</title>
<author role="aut"> <persName> <forename type="first">Margot</forename>
<surname>Fournier</surname>
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<email type="domain">chuv.ch</email>
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<author role="aut"> <persName> <forename type="first">Amandine</forename>
<surname>Roux</surname>
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<email type="domain">wanadoo.fr</email>
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</author>
<author role="aut"> <persName> <forename type="first">Jérôme</forename>
<surname>Garrigue</surname>
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<email type="md5">b3ae68c79ec40e16ab5334c88d2cc2e9</email>
<email type="domain">upmc.fr</email>
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<author role="aut"> <persName> <forename type="first">Marie-Paule</forename>
<surname>Muriel</surname>
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<email type="md5">2ac0769318adf054dfee4958f15fbb57</email>
<email type="domain">upmc.fr</email>
<idno type="halauthorid">942686</idno>
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<author role="aut"> <persName> <forename type="first">Paul</forename>
<surname>Blanche</surname>
</persName>
<email type="md5">70cf7a37777789d9907018beeeb095c7</email>
<email type="domain">isped.u-bordeaux2.fr</email>
<idno type="idhal" notation="string">paul-blanche</idno>
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<author role="aut"> <persName> <forename type="first">Hilal</forename>
<surname>Lashuel</surname>
</persName>
<email type="md5">ecf459d9b90670a7a4aca088838f3483</email>
<email type="domain">epfl.ch</email>
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</author>
<author role="aut"> <persName> <forename type="first">John</forename>
<surname>Anderson</surname>
</persName>
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<author role="aut"> <persName> <forename type="first">Robin</forename>
<surname>Barbour</surname>
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<email type="md5">a636993be76f78483b1fd63a50b632b7</email>
<email type="domain">elan.com</email>
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<author role="aut"> <persName> <forename type="first">Jiping</forename>
<surname>Huang</surname>
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<email type="md5">c907bf2e5c5b83e4c039227dbf75f1af</email>
<email type="domain">elan.com</email>
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<author role="aut"> <persName> <forename type="first">Sophie</forename>
<surname>Tezenas Du Montcel</surname>
</persName>
<email type="md5">c2bf0b80a7ce79ae5ae008369e5a3e12</email>
<email type="domain">psl.aphp.fr</email>
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<affiliation ref="#struct-15366"></affiliation>
</author>
<author role="aut"> <persName> <forename type="first">Alexis</forename>
<surname>Brice</surname>
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<email type="md5">ea06b61f8a5e647b8d1798e1cad02214</email>
<email type="domain">upmc.fr</email>
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<author role="crp"> <persName> <forename type="first">Olga</forename>
<surname>Corti</surname>
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<email type="domain">upmc.fr</email>
<idno type="halauthorid">903309</idno>
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<monogr> <idno type="halJournalId" status="VALID">351</idno>
<idno type="issn">1471-2202</idno>
<idno type="eissn">1471-2202</idno>
<title level="j">BMC Neuroscience</title>
<imprint> <publisher>BioMed Central</publisher>
<biblScope unit="volume">14</biblScope>
<biblScope unit="issue">1</biblScope>
<biblScope unit="pp">135</biblScope>
<date type="datePub">2013-11-05</date>
<date type="dateEpub">2013-11-05</date>
</imprint>
</monogr>
<idno type="doi">10.1186/1471-2202-14-135</idno>
<idno type="pubmed">24192137</idno>
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<profileDesc> <langUsage> <language ident="en">English</language>
</langUsage>
<textClass> <keywords scheme="author"> <term xml:lang="en">α-syn phosphorylation</term>
<term xml:lang="en">α-syn truncation</term>
<term xml:lang="en">Ubiquitin</term>
<term xml:lang="en">Posttranslational modifications</term>
<term xml:lang="en">Transgenic mice overproducing α-syn</term>
<term xml:lang="en">parkin knockout mice</term>
<term xml:lang="en">Parkinson's disease</term>
</keywords>
<classCode scheme="halDomain" n="sdv.neu">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]</classCode>
<classCode scheme="halTypology" n="ART">Journal articles</classCode>
</textClass>
<abstract xml:lang="en">BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), alpha-synuclein (alpha-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against alpha-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human alpha-syn (hA30Palpha-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to alpha-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar alpha-syn species phosphorylated at S129 (PS129alpha-syn) were the predominant neuropathological feature in hA30Palpha-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and alpha-syn truncated at D135 (alpha-synD135), indicating that PS129alpha-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in alpha-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of alpha-syn deposits in end-stage disease.</abstract>
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