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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.
Acta Neuropathol Commun. 2017 Feb 01; 5(1):11.AN

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.

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Authors+Show Affiliations

Ip CW
Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany. ip_c@ukw.de.
Klaus LC
Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
Karikari AA
Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
Visanji NP
Morton and Gloria Shulman Movement Disorders Centre & Edmund J. Saffra Program in Parkinson's Disease, Toronto Western Hospital, Toronto Western Hospital, 399 Bathurst Street, 9MC 422, Toronto, ON, M5T 2S8, Canada.
Brotchie JM
Krembil Research Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, 8KD402, Toronto, ON, M5T 2S8, Canada.
Lang AE
Morton and Gloria Shulman Movement Disorders Centre & Edmund J. Saffra Program in Parkinson's Disease, Toronto Western Hospital, Toronto Western Hospital, 399 Bathurst Street, 9MC 422, Toronto, ON, M5T 2S8, Canada. Krembil Research Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, 8KD402, Toronto, ON, M5T 2S8, Canada. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada. Department of Medicine, University of Toronto, Toronto, ON, Canada.
Volkmann J
Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
Koprich JB
Krembil Research Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, 8KD402, Toronto, ON, M5T 2S8, Canada.

MeSH

AgedAged, 80 and overAnimalsCorpus StriatumDependovirusDopamineDopamine Plasma Membrane Transport ProteinsGenetic VectorsHomovanillic AcidHumansMaleMice, Inbred C57BLMotor ActivityMutationNerve DegenerationNeuronsParkinsonian DisordersSubstantia NigraTyrosine 3-Monooxygenasealpha-Synuclein

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28143577

Citation

Ip, Chi Wang, et al. "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." Acta Neuropathologica Communications, vol. 5, no. 1, 2017, p. 11.
Ip CW, Klaus LC, Karikari AA, et al. 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. Acta Neuropathol Commun. 2017;5(1):11.
Ip, C. W., Klaus, L. C., Karikari, A. A., Visanji, N. P., Brotchie, J. M., Lang, A. E., Volkmann, J., & Koprich, J. B. (2017). 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. Acta Neuropathologica Communications, 5(1), 11. https://doi.org/10.1186/s40478-017-0416-x
Ip CW, et al. 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. Acta Neuropathol Commun. 2017 Feb 1;5(1):11. PubMed PMID: 28143577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ip,Chi Wang, AU - Klaus,Laura-Christin, AU - Karikari,Akua A, AU - Visanji,Naomi P, AU - Brotchie,Jonathan M, AU - Lang,Anthony E, AU - Volkmann,Jens, AU - Koprich,James B, Y1 - 2017/02/01/ PY - 2016/12/25/received PY - 2017/01/27/accepted PY - 2017/2/2/entrez PY - 2017/2/2/pubmed PY - 2017/10/27/medline KW - A53T mutation KW - Lewy-like pathology KW - Mouse model KW - Parkinson’s disease KW - α-synuclein SP - 11 EP - 11 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 5 IS - 1 N2 - 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. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/28143577/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_ DB - PRIME DP - Unbound Medicine ER -
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