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

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.

Small Extracellular Vesicles Secreted by Nigrostriatal Astrocytes Rescue Cell Death and Preserve Mitochondrial Function in Parkinson's Disease

“…[104,105] Our data showing differential intrinsic and extrinsic responses of VMB-and STR-AS fit with the reported high level of AS heterogeneity in the CNS, whose regulatory mechanisms (e.g., transcriptional versus epigenetic programs) remain as outstanding open questions for the field. [77,129,133,134] Indeed, the molecular machinery which orchestrates the distinct EV secretion ratesaccording to the brain region and the specific exposure to inflammatory triggers-needs to be further elucidated. Also, these findings call for a deeper understanding of the functional implications of such a specific response to microenvironmental cues between VMB (where the DAergic neurons reside) versus STR (where they project) for the pathogenesis of PD and, eventually, for the development of new therapeutic avenues.…”

“…[40][41][42][44][45][46][47][48][49][50]73,89,94,127,128] Especially, the heterogeneous nature of AS has been emphasized, showing regional AS differential responses to both genetic and environmental factors, including ageing, inflammatory or neurotoxin exposures, all crucial conditions of vulnerability for PD. [40,41,44,45,73,81,88,129] Yet, the modality of the intricate AS-neuron crosstalk still remains undefined. Among the multiple modes of intercellular communication, the secretion of EVs has emerged as a powerful tool for the exchange of information.…”

Distribution of Lewy-related pathology in the brain, spinal cord, and periphery: the population-based Vantaa 85 + study

“…Imaging studies have also suggested two distinct temporal models of αSyn pathology progression [ 13 ]. Recent reports have indicated that there may be more structural heterogeneity of the αSyn protein in different synucleinopathies than previously understood [ 7 , 35 , 50 ] and it remains to be investigated whether this heterogeneity is linked to distinct temporal patterns of αSyn pathology progression.…”

Integration of O-GlcNAc into Stress Response Pathways

“…Highly enriched in presynaptic terminals, α-synuclein regulates vesicle fusion and neurotransmitter release in normal physiology [ 187 ]. Current research indicates that physiological α-synuclein is subject to dynamic equilibrium between an unstructured monomer and an α-helical multimer [ 188 , 189 , 190 ], with multimerization implicated in binding the synaptic vesicle membrane. Misfolded α-synuclein oligomers accumulate in neuropathology, causing progressive synaptic dysfunction, membrane permeabilization, prion-like cell-to-cell spreading, and eventual neuronal death.…”