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A toxic monomeric conformer of the polyglutamine protein

Nature Structural & Molecular Biology volume 14, pages 332–340 (2007)Cite this article

Abstract

Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a β-sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into β-sheet–rich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble β-sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic β-sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.

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Figure 1: The polyQ stretch contributes an α-helical structure to thio-polyQ fusion proteins.
Figure 2: The expanded thio-polyQ protein undergoes a conformational transition to a β-sheet–dominant structure, resulting in amyloid-like fibril formation.
Figure 3: The soluble thio-polyQ protein with a β-sheet–dominant structure is mainly a monomer.
Figure 4: The soluble β-sheet monomer of the expanded polyQ protein is cytotoxic.
Figure 5: QBP1 prevents the expanded polyQ protein monomer from undergoing the toxic β-sheet conformational transition, resulting in inhibition of amyloid-like fibril formation.
Figure 6: Proposed mechanisms of cytotoxicity of the expanded polyQ protein and its inhibition by QBP1.

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Acknowledgements

We thank J.R. Burke, W.J. Strittmatter, O. Onodera and H. Hiramatsu for helpful discussions, H. Matsushima, R. Sasaki, C. Ito, M. Sakai, A. Fukuhara, Y. Okamoto, T. Saiwaki, T. Sekimoto and Y. Yoneda for technical assistance, K. Akao (JASCO) for the FT-IR measurements and R. Hirota (RIBM) for the AFM image recordings. This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas (to Y.N.; Advanced Brain Science Project, Research on Pathomechanisms of Brain Disorders, Life of Proteins, and Water and Biomolecules) and the 21st Century COE program (to T.T.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; by Grants-in-Aid for Scientific Research (to Y.N. and T.I.) from the Japan Society for the Promotion of Science; and by a Grant-in-Aid for the Research Committee for Ataxic Diseases (to Y.N.) from the Ministry of Health, Labor and Welfare, Japan.

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Authors and Affiliations

  1. Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan

    Yoshitaka Nagai, H Akiko Popiel, Nobuhiro Fujikake & Tatsushi Toda

  2. Department of Molecular Biology and Cell Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, 599-8531, Japan

    Takashi Inui

  3. Department of Food and Nutrition, Tsu City College, Tsu, Mie, 514-0112, Japan

    Takashi Inui

  4. Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, 565-0874, Japan

    Takashi Inui & Yoshihiro Urade

  5. Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui, 910-1193, Japan

    Kazuhiro Hasegawa & Hironobu Naiki

  6. Division of Protein Structural Biology, Laboratory of Protein Folding, Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan

    Yuji Goto

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  1. Yoshitaka Nagai
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Contributions

Y.N. and T.I. designed the research. Y.N., T.I., H.A.P. and N.F. performed the biochemical and cell culture experiments. K.H. and H.N. performed the EM experiments. Y.U. provided the CD spectropolarimeter. Y.G. performed the analytical ultracentrifugation experiments. Y.N., T.I. and T.T. wrote the paper.

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Correspondence to Yoshitaka Nagai or Tatsushi Toda.

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Nagai, Y., Inui, T., Popiel, H. et al. A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 14, 332–340 (2007). https://doi.org/10.1038/nsmb1215

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