Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity

Authors

  • Gaofeng Dong,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Kylie Gross,

    1. Department of Biology, Mount Marty College, Yankton, South Dakota, USA
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  • Fangfang Qiao,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Justine Ferguson,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Eduardo A. Callegari,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Khosrow Rezvani,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Dong Zhang,

    1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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  • Christian J. Gloeckner,

    1. Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit for Protein Science, Neuherberg, Germany
    2. Institute for Ophthalmic Research, Medical Proteome Center, University of Tubingen, Tubingen, Germany
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  • Marius Ueffing,

    1. Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit for Protein Science, Neuherberg, Germany
    2. Institute for Ophthalmic Research, Medical Proteome Center, University of Tubingen, Tubingen, Germany
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  • Hongmin Wang

    Corresponding author
    • Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
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Address correspondence and reprint requests to Dr. Hongmin Wang, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.

E-mail: Hongmin.Wang@usd.edu

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expansion of CAG trinucleotide repeats encoding for polyglutamine (polyQ) in the huntingtin (Htt) gene. Despite considerable effort, the mechanisms underlying the toxicity of the mutated Htt protein remains largely uncertain. To identify novel therapeutic targets, we recently employed the approach of tandem affinity purification and discovered that calretinin (Cr), a member of the EF-hand family of calcium-binding proteins, is preferentially associated with mHtt, although it also interacts with wild-type Htt. These observations were supported by coimmunoprecipitation and by colocalization of Cr with mHtt in neuronal cultures. Over- expression of Cr reduced mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD, whereas knockdown of Cr expression in the cells enhanced mHtt-caused neuronal cell death. In addition, over-expression of Cr was also associated with reduction of intracellular free calcium and activation of Akt. These results suggest that Cr may be a potential therapeutic target for treatment of HD.

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