a-Synuclein Conformational Strains as Drivers of Phenotypic Heterogeneity in Neurodegenerative Diseases

The synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies, and multiple sys-tem atrophy, are a class of human neurodegenerative disorders unified by the presence of a-synuclein aggregates in the brain. Considerable clinical and pathological heterogeneity exists within and among the individual synucleinopathies. A potential explanation for this variability is the existence of distinct con-formational strains of a-synuclein aggregates that cause different disease manifestations. Like prion strains, a-synuclein strains can be delineated based on their structural architecture, with structural differ-ences among a-synuclein aggregates leading to unique biochemical attributes and neuropathological properties in humans and animal models. Bolstered by recent high-resolution structural data from patient brain-derived material, it has now been firmly established that there are conformational differences among a-synuclein aggregates from different human synucleinopathies. Moreover, recombinant a-synuclein can be polymerized into several structurally distinct aggregates that exhibit unique pathological properties. In this review, we outline the evidence supporting the existence of a-synuclein strains and highlight how they can act as drivers of phenotypic heterogeneity in the human synucleinopathies.& COPY; 2023 Elsevier Ltd. All rights reserved.