AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson’s disease
Identifieur interne : 000127 ( Main/Exploration ); précédent : 000126; suivant : 000128AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson’s disease
Auteurs : Chi Wang Ip [Allemagne] ; Laura-Christin Klaus [Allemagne] ; Akua A. Karikari [Allemagne] ; Naomi P. Visanji ; Jonathan M. Brotchie ; Anthony E. Lang ; Jens Volkmann [Allemagne] ; James B. KoprichSource :
- Acta Neuropathologica Communications [ 2051-5960 ] ; 2017.
Abstract
α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson’s disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 1012 gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33% reduction in TH+ dopaminergic nigral neurons (
Url:
DOI: 10.1186/s40478-017-0416-x
PubMed: 28143577
PubMed Central: 5286802
Affiliations:
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Karikari</name><affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1378 7891</institution-id><institution-id institution-id-type="GRID">grid.411760.5</institution-id><institution>Department of Neurology,</institution><institution>University Hospital of Würzburg,</institution></institution-wrap>Josef-Schneider-Strasse 11, 97080 Würzburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Josef-Schneider-Strasse 11, 97080 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Visanji, Naomi P" sort="Visanji, Naomi P" uniqKey="Visanji N" first="Naomi P." last="Visanji">Naomi P. Visanji</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0012 4167</institution-id><institution-id institution-id-type="GRID">grid.417188.3</institution-id><institution>Morton and Gloria Shulman Movement Disorders Centre & Edmund J. Saffra Program in Parkinson’s Disease,</institution><institution>Toronto Western Hospital, Toronto Western Hospital,</institution></institution-wrap>399 Bathurst Street, 9MC 422, Toronto, ON M5T 2S8 Canada</nlm:aff><wicri:noCountry code="subfield">ON M5T 2S8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0474 0428</institution-id><institution-id institution-id-type="GRID">grid.231844.8</institution-id><institution>Krembil Research Institute, Toronto Western Hospital,</institution><institution>University Health Network,</institution></institution-wrap>60 Leonard Avenue, 8KD402, Toronto, ON M5T 2S8 Canada</nlm:aff><wicri:noCountry code="subfield">ON M5T 2S8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0012 4167</institution-id><institution-id institution-id-type="GRID">grid.417188.3</institution-id><institution>Morton and Gloria Shulman Movement Disorders Centre & Edmund J. Saffra Program in Parkinson’s Disease,</institution><institution>Toronto Western Hospital, Toronto Western Hospital,</institution></institution-wrap>399 Bathurst Street, 9MC 422, Toronto, ON M5T 2S8 Canada</nlm:aff><wicri:noCountry code="subfield">ON M5T 2S8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0474 0428</institution-id><institution-id institution-id-type="GRID">grid.231844.8</institution-id><institution>Krembil Research Institute, Toronto Western Hospital,</institution><institution>University Health Network,</institution></institution-wrap>60 Leonard Avenue, 8KD402, Toronto, ON M5T 2S8 Canada</nlm:aff><wicri:noCountry code="subfield">ON M5T 2S8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution>Tanz Centre for Research in Neurodegenerative Diseases,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, ON Canada</nlm:aff><wicri:noCountry code="subfield">ON Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution>Department of Medicine,</institution><institution>University of Toronto,</institution></institution-wrap>Toronto, ON Canada</nlm:aff><wicri:noCountry code="subfield">ON Canada</wicri:noCountry></affiliation></author><author><name sortKey="Volkmann, Jens" sort="Volkmann, Jens" uniqKey="Volkmann J" first="Jens" last="Volkmann">Jens Volkmann</name><affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 1378 7891</institution-id><institution-id institution-id-type="GRID">grid.411760.5</institution-id><institution>Department of Neurology,</institution><institution>University Hospital of Würzburg,</institution></institution-wrap>Josef-Schneider-Strasse 11, 97080 Würzburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Josef-Schneider-Strasse 11, 97080 Würzburg</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0474 0428</institution-id><institution-id institution-id-type="GRID">grid.231844.8</institution-id><institution>Krembil Research Institute, Toronto Western Hospital,</institution><institution>University Health Network,</institution></institution-wrap>60 Leonard Avenue, 8KD402, Toronto, ON M5T 2S8 Canada</nlm:aff><wicri:noCountry code="subfield">ON M5T 2S8 Canada</wicri:noCountry></affiliation></author></analytic><series><title level="j">Acta Neuropathologica Communications</title><idno type="eISSN">2051-5960</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson’s disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10<sup>12</sup> gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33% reduction in TH+ dopaminergic nigral neurons (<italic>P</italic> < 0.001), 29% deficit in striatal DAT binding (<italic>P</italic> < 0.05), 38% and 33% reductions in dopamine (<italic>P</italic> < 0.001) and DOPAC (<italic>P</italic> < 0.01) levels and a 60% increase in dopamine turnover (homovanilic acid/dopamine ratio; <italic>P</italic> < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (<italic>P</italic> < 0.001; <italic>P</italic> < 0.05). These data show that unilateral injection of AAV1/2-A53T α-synuclein into the mouse SN leads to persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system and development of Lewy-like pathology, thereby reflecting clinical and pathological hallmarks of human PD.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Abeliovich, A" uniqKey="Abeliovich A">A Abeliovich</name></author><author><name sortKey="Schmitz, Y" uniqKey="Schmitz Y">Y Schmitz</name></author><author><name sortKey="Farinas, I" uniqKey="Farinas I">I Farinas</name></author><author><name sortKey="Choi Lundberg, D" uniqKey="Choi Lundberg D">D Choi-Lundberg</name></author><author><name sortKey="Ho, Wh" uniqKey="Ho W">WH Ho</name></author><author><name sortKey="Castillo, Pe" uniqKey="Castillo P">PE Castillo</name></author><author><name sortKey="Shinsky, N" uniqKey="Shinsky N">N Shinsky</name></author><author><name sortKey="Verdugo, Jm" uniqKey="Verdugo J">JM Verdugo</name></author><author><name sortKey="Armanini, M" uniqKey="Armanini M">M Armanini</name></author><author><name sortKey="Ryan, A" uniqKey="Ryan A">A Ryan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beach, Tg" uniqKey="Beach T">TG Beach</name></author><author><name sortKey="White, Cl" uniqKey="White C">CL White</name></author><author><name sortKey="Hamilton, Rl" uniqKey="Hamilton R">RL Hamilton</name></author><author><name sortKey="Duda, Je" uniqKey="Duda J">JE Duda</name></author><author><name sortKey="Iwatsubo, T" uniqKey="Iwatsubo T">T Iwatsubo</name></author><author><name sortKey="Dickson, Dw" uniqKey="Dickson D">DW Dickson</name></author><author><name sortKey="Leverenz, Jb" uniqKey="Leverenz J">JB Leverenz</name></author><author><name sortKey="Roncaroli, F" uniqKey="Roncaroli F">F Roncaroli</name></author><author><name sortKey="Buttini, M" uniqKey="Buttini M">M Buttini</name></author><author><name 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Vandenberghe</name></author><author><name sortKey="Wilson, Jm" uniqKey="Wilson J">JM Wilson</name></author><author><name sortKey="Debyser, Z" uniqKey="Debyser Z">Z Debyser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yasuda, T" uniqKey="Yasuda T">T Yasuda</name></author><author><name sortKey="Nihira, T" uniqKey="Nihira T">T Nihira</name></author><author><name sortKey="Ren, Yr" uniqKey="Ren Y">YR Ren</name></author><author><name sortKey="Cao, Xq" uniqKey="Cao X">XQ Cao</name></author><author><name sortKey="Wada, K" uniqKey="Wada K">K Wada</name></author><author><name sortKey="Setsuie, R" uniqKey="Setsuie R">R Setsuie</name></author><author><name sortKey="Kabuta, T" uniqKey="Kabuta T">T Kabuta</name></author><author><name sortKey="Wada, K" uniqKey="Wada K">K Wada</name></author><author><name sortKey="Hattori, N" uniqKey="Hattori N">N Hattori</name></author><author><name sortKey="Mizuno, Y" uniqKey="Mizuno Y">Y Mizuno</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bavière</li><li>District de Basse-Franconie</li></region><settlement><li>Wurtzbourg</li></settlement></list><tree><noCountry><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name><name sortKey="Visanji, Naomi P" sort="Visanji, Naomi P" uniqKey="Visanji N" first="Naomi P." last="Visanji">Naomi P. Visanji</name></noCountry><country name="Allemagne"><region name="Bavière"><name sortKey="Ip, Chi Wang" sort="Ip, Chi Wang" uniqKey="Ip C" first="Chi Wang" last="Ip">Chi Wang Ip</name></region><name sortKey="Karikari, Akua A" sort="Karikari, Akua A" uniqKey="Karikari A" first="Akua A." last="Karikari">Akua A. Karikari</name><name sortKey="Klaus, Laura Christin" sort="Klaus, Laura Christin" uniqKey="Klaus L" first="Laura-Christin" last="Klaus">Laura-Christin Klaus</name><name sortKey="Volkmann, Jens" sort="Volkmann, Jens" uniqKey="Volkmann J" first="Jens" last="Volkmann">Jens Volkmann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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