⍺-Synuclein Structural Diversity and the Cellular Environment in ⍺-Synuclein Transmission Models and Humans

Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are termed synucleinopathies, disorders that are characterized by the intracellular aggregation of the protein ɑ-synuclein. The cellular tropism of synuclein pathology in these syndromes is notably distinct since in the Lewy disorders, PD and DLB, ɑSyn forms aggregates in neurons whereas in MSA ɑSyn forms aggregates in oligodendrocytes. Studies examining ɑSyn pathology in experimental models and in human brain have now identified fibrillar ɑSyn with unique but distinct molecular signatures, suggesting that the structure of these ɑSyn fibrils might be closely tied to their cellular ontogeny. In contrast to the native structural heterogeneity of ɑSyn in vitro, the conformational landscape of fibrillar ɑSyn in human brain and in vivo transmission models appears to be remarkably uniform. Here, we review the studies by which we propose a hypothesis that the cellular host environment might be in part responsible for how ɑSyn filaments assemble into phenotype-specific strains. We postulate that the maturation of ɑSyn strains develops as a function of their in vivo transmission routes and cell-specific risk factors. The impact of the cellular environment on the structural diversity of ɑSyn might have important implications for the design of preclinical studies and their use for the development of ɑSyn-based biomarkers and therapeutic strategies. By combining phenotype-specific fibrils and relevant synucleinopathy transmission models, preclinical models might more closely reflect unique disease phenotypes.