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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

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dc.contributor.author Ip, Chi Wang
dc.contributor.author Klaus, Laura-Christin
dc.contributor.author Karikari, Akua A.
dc.contributor.author Visanji, Naomi P.
dc.contributor.author Brotchie, Jonathan M.
dc.contributor.author Lang, Anthony E.
dc.contributor.author Volkmann, Jens
dc.contributor.author Koprich, James B.
dc.date.accessioned 2023-09-30T11:07:55Z
dc.date.available 2023-09-30T11:07:55Z
dc.date.issued 2017
dc.identifier.uri http://hdl.handle.net/123456789/8777
dc.description.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 (P < 0.001), 29% deficit in striatal DAT binding (P < 0.05), 38% and 33% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 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 (P < 0.001; P < 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. en_US
dc.language.iso en en_US
dc.publisher University of Cape Coast en_US
dc.subject Parkinson’s disease en_US
dc.subject α-synuclein en_US
dc.subject A53T mutation en_US
dc.subject Mouse model en_US
dc.subject Lewy-like pathology en_US
dc.title 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 en_US
dc.type Article en_US


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