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Publication Detail
Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations
  • Publication Type:
    Journal article
  • Authors:
    De Boni L, Watson AH, Zaccagnini L, Wallis A, Zhelcheska K, Kim N, Sanderson J, Jiang H, Martin E, Cantlon A, Rovere M, Liu L, Sylvester M, Lashley T, Dettmer U, Jaunmuktane Z, Bartels T
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
  • Journal:
    Acta Neuropathologica
  • Medium:
  • Status:
  • Country:
  • PII:
  • Language:
  • Keywords:
    Aggregation, Aggregation transmission, DLB, Multimers, PD, α-Synuclein
  • Notes:
    This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible “prion-like” propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a “prion-like” aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and “prion-like” aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.
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