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Mortalin inhibition in experimental Parkinson's disease

Authors

  • Davide Chiasserini PhD,

    1. Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
    2. Fondazione S. Lucia—I.R.C.C.S., Rome, Italy
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  • Alessandro Tozzi PhD,

    1. Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
    2. Fondazione S. Lucia—I.R.C.C.S., Rome, Italy
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  • Antonio de Iure PhD,

    1. Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
    2. Fondazione S. Lucia—I.R.C.C.S., Rome, Italy
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  • Michela Tantucci PhD,

    1. Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
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  • Federica Susta PhD,

    1. Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy
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  • Pier Luigi Orvietani MSc,

    1. Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy
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  • Keizo Koya PhD,

    1. Synta Pharmaceuticals Corp., Lexington, Massachusetts, USA
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  • Luciano Binaglia PhD,

    1. Dipartimento di Medicina Interna, Sezione di Biochimica, Università di Perugia, Perugia, Italy
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  • Paolo Calabresi MD

    Corresponding author
    1. Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy
    2. Fondazione S. Lucia—I.R.C.C.S., Rome, Italy
    • Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156 Perugia, Italy
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  • Relevant conflicts of interest/financial disclosures: Nothing to report. The present work was supported by grants from the European Community (EC) contract number 222918 (REPLACES) FP7—Thematic priority HEALTH (to P.C.), Progetto Strategico 2007 (to P.C.), Progetti Finalizzati Multicentrici Programma Neuroscienze Compagnia di San Paolo (to P.C.), and Progetti di Ricerca di Interesse Nazionale (PRIN 2008; to P.C.). Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine–denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine–treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. © 2011 Movement Disorder Society

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