SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition

Abstract

Aims/ hypothesisSorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in pancreatic islet beta cells, yet the role of SORLA in islets is unclear so far. Based on its protective role in reducing amyloid burden in the brain, we hypothesized that SORLA may have a similar function in the pancreas, regulating islet amyloid plaque formation from islet amyloid polypeptide (IAPP). MethodsWe generated human IAPP transgenic mice lacking SORLA (hIAPP:SORLA KO) to assess the consequences of receptor deficiency for islet histopathology and function in vivo. Using both primary islet cells and established cell lines, we further investigated the molecular mechanisms whereby SORLA controls the cellular metabolism and accumulation of IAPP. ResultsLoss of SORLA activity in hIAPP:SORLA KO resulted in a significant increase in islet amyloid deposits and associated islet cell death as compared to hIAPP:SORLA WT animals expressing the receptor. Aggravated islet amyloid deposition was observed in mice fed a normal chow diet, not requiring high-fat diet feeding typically needed to induce islet amyloidosis in mouse models. Further in vitro studies showed that SORLA binds to and mediates the endocytic uptake of proIAPP, but not mature IAPP, delivering the propeptide to an endolysosomal fate. Conclusions/interpretationSORLA functions as a clearance receptor specific for proIAPP, protecting against islet amyloid deposition and associated cell death caused by IAPP.