Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations

• Main Authors: Bartels, T. (Author), Cantlon, A. (Author), de Boni, L. (Author), Dettmer, U. (Author), Jaunmuktane, Z. (Author), Jiang, H. (Author), Kim, N. (Author), Lashley, T. (Author), Liu, L. (Author), Martin, E. (Author), Rovere, M. (Author), Sanderson, J. (Author), Sylvester, M. (Author), Wallis, A. (Author), Watson, A.H (Author), Zaccagnini, L. (Author), Zhelcheska, K. (Author)
• Format: Article
• Language: English
• Published: Springer Science and Business Media Deutschland GmbH 2022
• Subjects: Aggregation; Aggregation transmission; DLB; Multimers; PD; α-Synuclein
• Online Access: View Fulltext in Publisher
• Physical Description: 17
• ISBN: 00016322 (ISSN)
• DOI: 10.1007/s00401-022-02406-7

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. © 2022, The Author(s).