α-Synuclein Structural Diversity and the Cellular Environment in α-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 alpha-synuclein. The cellular tropism of synuclein pathology in these syndromes is notably distinct since in the Lewy disorders, PD and DLB, alpha Syn forms aggregates in neurons whereas in MSA alpha Syn forms aggregates in oligodendrocytes. Studies examining alpha Syn pathology in experimental models and in human brain have now identified fibrillar alpha Syn with unique but distinct molecular signatures, suggesting that the structure of these alpha Syn fibrils might be closely tied to their cellular ontogeny. In contrast to the native structural heterogeneity of alpha Syn in vitro, the conformational landscape of fibrillar alpha Syn 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 alpha Syn filaments assemble into phenotype-specific strains. We postulate that the maturation of alpha Syn 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 alpha Syn might have important implications for the design of preclinical studies and their use for the development of alpha Syn-based biomarkers and therapeutic strategies. By combining phenotype-specific fibrils and relevant synucleinopathy transmission models, preclinical models might more closely reflect unique disease phenotypes.