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.
Highlights
The protein α-synuclein is the major constituent of pathological neuronal inclusions both in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [56].Despite initially being characterized as natively unfolded, data collected in the last decade suggest that αS can exhibit different conformations under physiological conditions, which in turn help in governing aggregation propensity
Our current findings provide a novel mechanism, in which the equilibrium of physiological aggregation-resistant αS multimers and physiological, aggregation-prone αS monomers is disturbed in sporadic PD and DLB patients, governing the regions affected in the brain and clinical outcome (Fig. 5)
Our study demonstrated that (i) αSH multimers are present in human post-mortem brain tissue and exhibit a physiological, helical secondary structure, making them resistant to spontaneous as well as “prion-like” amyloid aggregation; (ii) the disequilibrium of αSH and αSU is brain region specific and associated with the spreading theory of αS and with clinical features such as dementia
Summary
The protein α-synuclein (αS) is the major constituent of pathological neuronal inclusions both in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [56]. Despite initially being characterized as natively unfolded, data collected in the last decade suggest that αS can exhibit different conformations under physiological conditions, which in turn help in governing aggregation propensity. The cytosolic unfolded, monomeric form of αS (αSU) is Dementia Research Institute, University College London, London, UK. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, London, UK.
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