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

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

Acta neuropathologica (2022-02-11)
Laura de Boni, Aurelia Hays Watson, Ludovica Zaccagnini, Amber Wallis, Kristina Zhelcheska, Nora Kim, John Sanderson, Haiyang Jiang, Elodie Martin, Adam Cantlon, Matteo Rovere, Lei Liu, Marc Sylvester, Tammaryn Lashley, Ulf Dettmer, Zane Jaunmuktane, Tim Bartels
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-α-Synuclein Antibody, clone SOY1, clone SOY1, from mouse
Sigma-Aldrich
Anti-α-Synuclein Antibody, clone 2F12, clone 2F12, from mouse
Sigma-Aldrich
Anti-β-Tubulin III antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution