Modulation of - synuclein in vitro aggregation kinetics by its alternative splice isoforms

The misfolding and aggregation of alpha- synuclein is linked to a family of neurodegenerative disorders known as synucleinopathies, the most prominent of which is Parkinson's disease (PD). Understanding the aggregation process of alpha- synuclein from a mechanistic point of view is thus of key importance. SNCA, the gene encoding alpha- synuclein, comprises six exons and produces various isoforms through alternative splicing. The most abundant isoform is expressed as a 140 - amino acid protein (alpha Syn-140), while three other isoforms, alpha Syn-126, alpha Syn-112, and alpha Syn-98, are generated by skipping exon 3, exon 5, or both exons, respectively. In this study, we performed a detailed biophysical characterization of the aggregation of these four isoforms. We found that alpha Syn-112 and alpha Syn-98 exhibit accelerated aggregation kinetics compared to alpha Syn-140 and form distinct aggregate morphologies, as observed by transmission electron microscopy. Moreover, we observed that the presence of relatively small amounts of alpha Syn-112 accelerates the aggregation of alpha Syn-140, significantly reducing the aggregation half - time. These results indicate a potential role of alternative splicing in the pathological aggregation of alpha- synuclein and provide insights into how this process could be associated with the development of synucleinopathies.