Protein aggregation mechanisms in synucleinopathies: commonalities and differences

Synucleinopathies are characterized by the presence of different types of alpha-synuclein (AS)-positive inclusion in the brain. Thus, whereas Lewy bodies are the hallmark of Parkinson disease and dementia with Lewy bodies, glial and neuronal cytoplasmic inclusions are shown by multiple system atrophy. Because the main component of all these inclusions is conformationally modified AS, aggregation of the latter is thought to be a key pathogenic event in these diseases. Although very little information has been available on AS function and aggregation mechanisms until 2 years ago, recent investigations have greatly improved our understanding of the steps involved in the pathogenesis of synucleinopathies. Additionally, important insights into the specific molecular events (e.g. differential posttranslational modifications or isoform expression profiles) underlying each of these conditions have been gained. The present review summarizes our current knowledge of the commonalities and differences shown by protein aggregation mechanisms in the various synucleinopathies.