Low-abundance αSyn-112 promotes αSyn-140 aggregation in vitro and forms immunoreactive deposits in Parkinson’s disease brain tissue

The aggregation of α-synuclein (αSyn) is a molecular hallmark of Parkinson’s disease (PD) and other synucleinopathies. Understanding the molecular mechanisms that determine the aggregation of this protein may thus facilitate the development of disease-modifying therapies. While αSyn is most commonly expressed as a 140-residue protein (αSyn-140), recent evidence suggests an involvement of alternatively spliced αSyn isoforms in disease onset and progression. Here, we report and characterise the interaction between αSyn-140 and the aggregation-prone αSyn-112 variant, one of the most abundant αSyn splice isoforms. We found that amounts as low as 1% of αSyn-112 accelerate the nucleation and aggregation of αSyn-140. To further investigate this phenomenon, we employed MALDI-MS and NMR spectroscopy, confirming that αSyn-140 and αSyn-112 monomers interact strongly with one another. Furthermore, to assess the association of αSyn-112 with disease pathology, we performed immunohistochemical staining combined with confocal microscopy on PD brain samples. Thereby, we found an increase in the number as well as the area of αSyn-112 immunoreactive aggregates compared to healthy controls. These results illustrate how low-abundance αSyn splice isoforms can modulate the aggregation landscape of αSyn-140 and in turn contribute to the molecular heterogeneity of synucleinopathies.