α-Synuclein promotes IAPP fibril formation in vitro and β-cell amyloid formation in vivo in mice

• Main Authors: Marija Mucibabic, Pär Steneberg, Emmelie Lidh, Jurate Straseviciene, Agnieszka Ziolkowska, Ulf Dahl, Emma Lindahl, Helena Edlund
• Format: Article
• Language: English
• Published: Nature Publishing Group 2020-11-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-020-77409-z

Abstract Type 2 diabetes (T2D), alike Parkinson’s disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in β-cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (αSyn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in β-cells. Here we show that αSyn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, αSyn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of αSyn in hIAPPtg mice enhanced β-cell amyloid formation in vivo whereas β-cell amyloid formation was reduced in hIAPPtg mice on a Snca −/− background. Taken together, our findings provide evidence that αSyn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for αSyn in β-cell amyloid formation.