Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs

Alpha-synuclein (α-Syn) is a neuronal protein implicated in the pathogenesis of several neurodegenerative disorders collectively known as synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This article provides a comprehensive overview of the structural characteristics of α-Syn, emphasizing its fibrillar aggregation and the resulting polymorphic fibril forms. Using advances in cryo-electron microscopy, a diverse range of α-Syn fibril polymorphs has been elucidated, both from <i>in vitro</i> preparations and patient-derived brain samples. We further explore the impact of mutation and post-translational modifications-such as truncation and phosphorylation -on α-Syn structure and the unique polymorphs they induce. The article underscores the biological and pathological relevance of α-Syn polymorphism, highlighting how different structural strains may underlie the structural and pathological heterogeneity observed in synucleinopathies. Understanding the mechanisms driving polymorph formation is critical for deciphering disease progression and developing targeted therapeutic strategies.