Initiation and progression of α-synuclein pathology in Parkinson's disease

Abstract

α-Synuclein aggregation is a critical molecular process that underpins the pathogenesis of Parkinson's disease. Aggregates may originate at synaptic terminals as a consequence of aberrant interactions between α-synuclein and lipids or evasion of proteostatic defences. The nature of these interactions is likely to influence the emergence of conformers or strains that in turn could explain the clinical heterogeneity of Parkinson's disease and related α-synucleinopathies. For neurodegeneration to occur, α-synuclein assemblies need to exhibit seeding competency, i.e. ability to template further aggregation, and toxicity which is at least partly mediated by interference with synaptic vesicle or organelle homeostasis. Given the dynamic and reversible conformational plasticity of α-synuclein, it is possible that seeding competency and cellular toxicity are mediated by assemblies of different structure or size along this continuum. It is currently unknown which α-synuclein assemblies are the most relevant to the human condition but recent advances in the cryo-electron microscopic characterisation of brain-derived fibrils and their assessment in stem cell derived and animal models are likely to facilitate the development of precision therapies or biomarkers. This review summarises the main principles of α-synuclein aggregate initiation and propagation in model systems, and their relevance to clinical translation.

Keywords: Fibril; Lewy body; Neurodegeneration; Oligomers; Propagation; Strains.

Fig. 1

Bi-directional equilibrium between α-synuclein conformational states. A α-Synuclein acquires a partially folded α-helical structure when bound to lipid membranes but is natively unfolded in solution. Under favourable conditions, unfolding of the N-terminus and exposure of the NAC domain triggers oligomerisation via partially folded intermediates. Oligomers convert into β-sheet containing protofibrils and highly ordered cross-β-sheet fibrillar polymorphs (strains). Distinct amino acid side chains exposed on the surface of each strain may lead to differential post-translation modifications (PTM) or protein interactions. By differentially evading protective factors or disrupting functional protein complexes such interactions may explain variance in strain toxicity, cellular vulnerability and potentially disease severity. B Focal accumulation of α-synuclein on or around membranes due to impaired turnover, mutations, post-translational modifications or changes in lipid composition could initiate misfolding and assembly of toxic oligomers. Amyloidogenic oligomers disrupt membrane integrity, causing local changes in pH or Ca²⁺ levels that promote fibril formation and disruption of organelle function