Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers

Abstract

Alpha-synuclein aggregation is thought to be a key event in the pathogenesis of synucleinopathies. Although different alpha-synuclein alterations and modifications have been proposed to be responsible for early aggregation steps, the mechanisms underlying these events remain unclarified. Alpha-synuclein is a small protein localized to synaptic terminals and its intrinsic structure has been claimed to be an important factor for self-oligomerization and self-aggregation. Alpha-synuclein expression studies in cell cultures have demonstrated that posttranslational modifications, such as phosphorylation, oxidation, and sumoylation, are primarily involved in alpha-synuclein aggregation. Furthermore, in the last few years accumulating evidence has pointed to alternative splicing as a crucial mechanism in the development of neurodegenerative disorders. At least three different alpha-synuclein isoforms have been described as products of alternative splicing. Two of these isoforms (alpha-synuclein 112 and alpha-synuclein 126) are shorter proteins with probably altered functions and aggregation propensity. The present review attempts to summarize the data so far available on alpha-synuclein structure, posttranslational modifications, and alternative splicing as possible enhancers of aggregation.