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A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain

Author

Listed:
  • Masayo Fujita

    (Tokyo Metropolitan Institute for Neuroscience)

  • Shuei Sugama

    (Tokyo Metropolitan Institute for Neuroscience)

  • Kazunari Sekiyama

    (Tokyo Metropolitan Institute for Neuroscience)

  • Akio Sekigawa

    (Tokyo Metropolitan Institute for Neuroscience)

  • Tohru Tsukui

    (Research Center for Genomic Medicine, Saitama Medical University)

  • Masaaki Nakai

    (Tokyo Metropolitan Institute for Neuroscience)

  • Masaaki Waragai

    (Tokyo Metropolitan Institute for Neuroscience)

  • Takato Takenouchi

    (Tokyo Metropolitan Institute for Neuroscience
    Transgenic Animal Research Center, National Institute of Agrobiological Sciences)

  • Yoshiki Takamatsu

    (Tokyo Metropolitan Institute for Neuroscience)

  • Jianshe Wei

    (Tokyo Metropolitan Institute for Neuroscience)

  • Edward Rockenstein

    (University of California-San Diego)

  • Albert R. LaSpada

    (University of California-San Diego
    University of California-San Diego
    University of California-San Diego
    Institute for Genomic Medicine, University of California-San Diego)

  • Eliezer Masliah

    (University of California-San Diego)

  • Satoshi Inoue

    (Research Center for Genomic Medicine, Saitama Medical University
    Graduate School of Medicine, The University of Tokyo)

  • Makoto Hashimoto

    (Tokyo Metropolitan Institute for Neuroscience)

Abstract

The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies.

Suggested Citation

  • Masayo Fujita & Shuei Sugama & Kazunari Sekiyama & Akio Sekigawa & Tohru Tsukui & Masaaki Nakai & Masaaki Waragai & Takato Takenouchi & Yoshiki Takamatsu & Jianshe Wei & Edward Rockenstein & Albert R., 2010. "A β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain," Nature Communications, Nature, vol. 1(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1101
    DOI: 10.1038/ncomms1101
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    Cited by:

    1. Vanessa C Ducas & Elizabeth Rhoades, 2014. "Investigation of Intramolecular Dynamics and Conformations of α-, β- and γ-Synuclein," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-10, January.

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