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Parkin-Knockout Mice did not Display Increased Vulnerability to Intranasal Administration of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

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Abstract

The loss of nigral dopaminergic neurons in Parkinson’s disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, the hybrid 129Sv-C57BL/6 parkin-deficient mice did not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to neurotoxicity induced by 6-hydroxydopamine (6-OHDA) or intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We aimed to re-evaluate the role of parkin in a pure C57BL/6 background after an acute intranasal (i.n.) MPTP administration, a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. We found that the deficiency of parkin gene modifies the d-amphetamine-induced locomotion in saline-treated animals. Intranasal MPTP induced Parkinsonism in parkin+/+ mice, through depletion of striatal dopamine, decreased number of dopaminergic neurons in the substantia nigra, and decreased d-amphetamine-induced hyperlocomotion. Additionally, the deletion of the parkin gene in a pure C57BL/6 background did not lead to increased vulnerability to i.n. MPTP-induced neurotoxicity. Moreover, the i.n. MPTP induced nigral astrogliosis predominantly in the pars reticulata in wild type and parkin−/− mice. Taken together, these results showed that the absence of parkin did not modify the vulnerability of nigrostriatal dopaminergic pathway after i.n. MPTP intoxication, suggesting that independently of mouse strain, the endogenous parkin is not required for protection of this system. These findings also suggest that the development of familial parkin-linked PD is not associated with exposure to environmental factors that specifically affects the dopaminergic system.

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Acknowledgments

The authors gratefully thank the financial support and grants provided by the brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), CAPES-COFECUB (France/Brazil; 681/2010), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa Ciência sem Fronteiras (CsF), and Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC). This work was also supported by Fondation de France, ANR-MNP, Fondation ICM, and “Investissements d’avenir” ANR-10-IAIHU-06.

Conflict of interest

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no financial or personal conflicts of interest related to this study.

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Authors and Affiliations

  1. INSERM UMR 975 (ex U679)—CNRS UMR 7225, Hôpital de la Salpêtrière—Bâtiment, ICM (Centre de Recheche de l’Institut du Cerveau et de la Moelle épinière), CRICM, Thérapeutique Expérimentale de la Neurodégénérescence, Université Pierre et Marie Curie, UPMC, 47 Boulevard de l’Hôpital, 75651, Paris, France

    Fabrine S. M. Tristão, Majid Amar, Olga Corti & Rita Raisman-Vozari

  2. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil

    Aderbal S. Aguiar Jr. & Rui D. Prediger

  3. INSERM UMR S894, Centre de Psychiatrie et Neuroscience, Université Pierre et Marie Curie, UPMC, Paris, France

    Caroline Chevarin, Laurence Lanfumey & Raymond Mongeau

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  1. Aderbal S. Aguiar Jr.
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  2. Fabrine S. M. Tristão
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  3. Majid Amar
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  4. Caroline Chevarin
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  5. Laurence Lanfumey
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  6. Raymond Mongeau
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  7. Olga Corti
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  8. Rui D. Prediger
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  9. Rita Raisman-Vozari
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Corresponding author

Correspondence to Rita Raisman-Vozari.

Additional information

Aderbal S. Aguiar and Fabrine S. M. Tristão contributed equally to this study.

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Aguiar, A.S., Tristão, F.S.M., Amar, M. et al. Parkin-Knockout Mice did not Display Increased Vulnerability to Intranasal Administration of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res 24, 280–287 (2013). https://doi.org/10.1007/s12640-013-9389-0

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  • DOI: https://doi.org/10.1007/s12640-013-9389-0

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