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

Abstract

The α-synuclein protein (αS) is the major constituent of pathological neuronal inclusions both in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) with differential brain region-specific pathology patterns and clinical presentations. Two hypotheses that were recently put forward were either that of brain-region specific vulnerability or that of different αS aggregates, “strains”, that would affect different brain regions via “prion-like” spread. What governs these patterns, their hypothesized “prion-like” progression and region-specific vulnerability to αS aggregation in different synucleinopathies is still largely unknown. Data collected in the last decade suggests that αS can exhibit in different conformations under physiological and/or pathological conditions, which in turn help govern aggregation propensity. The cytosolic unfolded, monomeric form of αS (αSCU) is aggregation-prone and can misfold into soluble, toxic oligomers, protofilaments, and amyloid fibrils with self-templating properties, while the cytosolic helically folded, multimeric form (αSCH) resists disease-associated changes.