Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes

Abstract

Aims/hypothesis Normal cellular prion protein (PrP C ) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrP C is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrP Sc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrP C localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrP C function through studies on interacting protein partners. Methods In order to evaluate localisation and trafficking of PrP C in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrP C expression in the human pancreas. Additionally, we performed PrP C -specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrP C mRNA levels leads to a concomitant increase in PrP C protein levels in human pancreases. Results In non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(−)] islets), we found PrP C in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrP C in alpha cells within diabetic INS(−) islets. We found PrP C localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrP C co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stressinducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrP C function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrP C ) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases. Conclusions/interpretation As the first study to address PrP C expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrP C in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrP C in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrP C in the human pancreas.

Correlates of circulating extracellular vesicle cargo with key clinical features of type 1 diabetes

“…In this context, it is of interest to highlight that recently, the Wasserfall group (48) showed an increased frequency of cellular prion proteins in pancreas specimens from people with T1D and that, earlier, Strom and collaborators (49) demonstrated in two rodent models that altered metabolism of cellular prion protein in β cells associated with glucose dysregulation.…”

“…In addition to the neutrophil, platelet, and immune cell activation related pathways, the differentially expressed proteins and phosphoproteins were enriched for other biological processes and KEGG pathways related to prion disease and multiple neurodegenerative diseases. In this context, it is of interest to highlight that recently, the Wasserfall group (48) showed an increased frequency of cellular prion proteins in pancreas specimens from people with T1D and that, earlier, Strom and collaborators (49) demonstrated in two rodent models that altered metabolism of cellular prion protein in β cells associated with glucose dysregulation.…”

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

“…Interestingly, in insulin-positive alpha and beta cells of patients with and without type 1 diabetes, PrP C was found in the plasma membrane and the ER but not in Golgi, possibly indicating UPS by the Golgi bypass. In this work, the authors suggest that the PrP C ’s Golgi bypass observed in the human pancreas could be through HSP70/DNAJC14 or GRASP55 ( Hiller et al, 2021 ). As aforementioned, PrP C associates with the HSP70/90 co-chaperone STI1/HOP in the cell surface ( Lopes et al, 2005 ; Rosenzweig et al, 2019 ), which could indicate a greater tendency of secretion to be via HSP70/DNAJC14, although this hypothesis must be tested and the mechanism for PrP C UPS needs to be clarified.…”

Cellular Prion Protein Is Closely Associated with Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma

“…There was a statistical significance between PrP C expression and DM. Although several studies demonstrated associations with PrP C and DM [ 37 , 38 , 39 ], there have been no reports that the expression of PrP C in HCC tissues is related to DM. Oskarsson et al demonstrated that intravenous injection of synthetic islet amyloid polypeptide (IAPP) aggregates can accelerate IAPP aggregate formation in islets in a rodent model of type 2 DM [ 40 ].…”