a-Synuclein oligomers and fibrils: partners in crime in synucleinopathies

The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of a-synuclein pathology. Moreover, a-synuclein fibrils have been recently reported to release soluble and highly toxic oligomeric species, responsible for an immediate dysfunction in the recipient neurons. In this review, we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused by a-synuclein oligomers and fibrils, both contributing to neurodegeneration in synucleinopathies.

Automated summary

The misfolding and aggregation of a-synuclein is the key feature of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. Soluble oligomeric assemblies formed during the early stages of aggregation are toxic to neurons, while fibrillar conformers contribute to the spreading of the pathology. Recent studies have also shown that a-synuclein fibrils release soluble and highly toxic oligomeric species, leading to immediate dysfunction in recipient neurons. This review discusses the mechanisms of cellular dysfunction caused by a-synuclein oligomers and fibrils in synucleinopathies.