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.
Highlights
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
We show that β-cells internalized exogenously administered αSyn and that tail-vein injection of αSyn into hIAPPtg mice enhanced β-cell amyloid formation whereas amyloid formation was reduced in hIAPPtg mice
Electron microscopy (TEM) analyses of double αSyn and Islet Amyloid Polypeptide (IAPP) immunogold labelled islets isolated from hIAPPtg mice and T2D individuals showed that, as previously described using the proximity-ligation-assay on human pancreatic sections[11], αSyn and IAPP coexists in close proximity in β-cells (Supplementary Fig. 1a-h). αSyn immunoreactivity was not observed when staining islets isolated from hIAPPtg mice on a Snca−/− backgound, demonstrating the specificity of the αSyn antibodies (Supplementary Fig. 2a,b)
Summary
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. 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. Aβ is the main component of Alzheimer’s plaques, both IAPP and an internal region of αSyn, denoted NAC, have been detected in Aβ d eposits[23,24] and Aβ fibrils has been suggested to seed IAPP a myloid[23], leaving open the possibility of cross-seeding between amyloidogenic peptides in vivo, which in turn may enhance the onset and/or progression of PMDs. Here we show that IAPP and αSyn co-localized in β-cell amyloid extracted from hIAPPtg mouse pancreases and human β-cells and that αSyn enhanced IAPP fibril formation in vitro in a dose-dependent manner. Our findings provide evidence for a role for αSyn in IAPP aggregation and β-cell amyloid formation
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