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Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

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Neurotherapeutics

Abstract

Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and the polyglutamine (polyQ) diseases, which are collectively called the “protein misfolding diseases”. In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration. Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1). We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro. Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases. We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains. Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases. We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases.

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Acknowledgments

We thank Shin-ichi Muramatsu, Shinya Oishi, Nobutaka Fujii, Takashi Inui, Osamu Onodera, and Mariano Carrion-Vazquez for their helpful discussions, and Nobuhiro Fujikake and Yuma Okamoto for their technical assistance. Our work on the polyglutamine diseases is supported, in part, by Grants-in-Aid for Scientific Research on Priority Areas (Advanced Brain Science Project, and Research on Pathomechanisms of Brain Disorders to Y.N.) and by a Comprehensive Brain Science Network Award for Young Scientists (to H.A.P.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; by Grants-in-Aid for Scientific Research (B) (to Y.N.), (C) (to H.A.P) and Challenging Exploratory Research (to Y.N.) from the Japan Society for the Promotion of Science, Japan; by a Grant-in-Aid for the Research Committee for Ataxic Diseases (to Y.N.) from the Ministry of Health, Labor and Welfare, Japan; and by a grant from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (CREST) (to Y.N.).

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Authors and Affiliations

  1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa Higashi, Kodaira, Tokyo, 187-8502, Japan

    H. Akiko Popiel, Toshihide Takeuchi, Keiji Wada & Yoshitaka Nagai

  2. Department of Medicine (Neurology) and Deane Laboratory, Duke University Medical Center, Durham, NC, 27710, USA

    James R. Burke & Warren J. Strittmatter

  3. Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Tatsushi Toda

  4. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, 332-0012, Japan

    Yoshitaka Nagai

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  1. H. Akiko Popiel
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  2. Toshihide Takeuchi
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  7. Yoshitaka Nagai
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Correspondence to Yoshitaka Nagai.

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Popiel, H.A., Takeuchi, T., Burke, J.R. et al. Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases. Neurotherapeutics 10, 440–446 (2013). https://doi.org/10.1007/s13311-013-0184-7

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