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Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation

Author

Listed:
  • Ulf Dettmer

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Andrew J. Newman

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Frank Soldner

    (The Whitehead Institute)

  • Eric S. Luth

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Nora C. Kim

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Victoria E. von Saucken

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • John B. Sanderson

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Rudolf Jaenisch

    (The Whitehead Institute
    Massachusetts Institute of Technology)

  • Tim Bartels

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

  • Dennis Selkoe

    (Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School)

Abstract

β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson’s disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.

Suggested Citation

  • Ulf Dettmer & Andrew J. Newman & Frank Soldner & Eric S. Luth & Nora C. Kim & Victoria E. von Saucken & John B. Sanderson & Rudolf Jaenisch & Tim Bartels & Dennis Selkoe, 2015. "Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8314
    DOI: 10.1038/ncomms8314
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    Cited by:

    1. Cheng Fu & Nan Yang & Jen-Zen Chuang & Nobuyuki Nakajima & Satoshi Iraha & Neeta Roy & Zhenquan Wu & Zhichun Jiang & Wataru Otsu & Roxana A. Radu & Howard Hua Yang & Maxwell Ping Lee & Tilla S. Worgal, 2024. "Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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