Dysglycemia and IAPP/alpha-synuclein cross-seeding: key triggers for beta-cell amyloid formation during development of Type 2 diabetes?

Type 2 diabetes (T2D) belongs to the group of protein misfolding diseases where aggregation and accumulation of misfolded proteins into amyloid is a hallmark.

Although, IAPP is the major aggregating peptide in β-cells, alpha-synuclein (aSyn), i.e. the major fibril component of Lewy bodies in Parkinson´s disease, is also expressed in pancreatic β-cells and aSyn levels are increased in β-cells of Ide-/- mice and in islets from T2D patients.

We now have data showing that aSyn and IAPP cross-seed and co-aggregate in vitro and in vivo and that high glucose concentrations enhance aSyn uptake in β-cells.

We hypothesize that elevated glucose levels stimulate cellular uptake and aggregation of IAPP and aSyn, thus provoking β-cell amyloid formation and T2D.

Using biochemical, cell biological, and in vivo animal studies we will address the: i) role of hyperglycemia in transmission and aggregation of IAPP and aSyn; ii) cellular mechanisms underlying uptake and aggregation of IAPP and aSyn in β-cells; iii) cross-seeding potential of IAPP and aSyn in vivo and the pathophysiological consequences thereof.

The proposed studies aim at a detailed mechanistic understanding of conditions and factor(s) that promote protein transmission, uptake, and aggregation of IAPP and aSyn in β-cells, which may expand our understanding of molecular mechanisms underlying protein aggregation and provide the basis for prevention and treatment of protein misfolding diseases.