Structural biology of alpha-synuclein amyloid filaments: Implications in synucleinopathies

Synucleinopathies are a group of neurodegenerative disorders characterized pathologically by the presence of neuronal and/or oligodendrocyte inclusions composed of aggregated alpha-synuclein (αS). These disorders can be divided into two major sub-types: Lewy body disease and multiple system atrophy, which have distinct clinical and pathological profiles. As is seen with other neurodegenerative diseases, recent evidences suggest that the conformation and molecular organization of αS amyloid filaments deposited in brains might dictate the distinct pathological and clinical profiles in synucleinopathies. Resolving the structure of disease-specific αS aggregates becomes, therefore, of clinical interest. Until recently, the specific conformations of these aggregates at molecular resolution have remained elusive. This is now possible due to the advent and development of cryo-electron microscopy (cryo-EM) technology. This review aims to cover the recent advances in the structural biology of αS amyloid filaments implicated in synucleinopathies, raising a number of critical questions that continue to be investigated. What can we learn from these structures? What are the main structural differences between experimental systems and human tissue derived protein aggregates? What factors drive these differences? Do the amplified assemblies represent faithfully the seed structures? How these new findings improve our understanding of the molecular mechanisms behind fibril formation in disease? Can this knowledge be exploited for the design of diagnostic and therapeutical strategies? These aspects and the recent advances in the field will be addressed and discussed in this work.