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

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 beta -cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (alpha Syn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in beta -cells. Here we show that alpha Syn, 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, alpha Syn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of alpha Syn in hIAPPtg mice enhanced beta -cell amyloid formation in vivo whereas beta -cell amyloid formation was reduced in hIAPPtg mice on a Snca (-/-) background. Taken together, our findings provide evidence that alpha Syn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for alpha Syn in beta -cell amyloid formation.