Pronounced cytosolic aggregation of cellular prion protein in pancreatic β-cells in response to hyperglycemia

Abstract

Cellular prion protein (PrPC), an N-linked glycoprotein, is expressed in a variety of tissues, but its functions remain unclear. PrP C is abundantly expressed in the endocrine pancreas, which regulates blood glucose homeostasis. Therefore, we investigated whether the expression of PrPC was altered in islets of Langerhans in a model of spontaneous type 1 diabetes, the diabetes-prone BioBreeding (BBdp) rat and a model of β-cell adaptation to hyperglycemia, the chronic glucose-infused Sprague Dawley rat. Pancreatic sections from animals aged 7-100 days were stained immunohistochemically and evaluated using light, fluorescence and confocal microscopy. PrPC was ubiquitously expressed in all four major endocrine cell types within islets. Surprisingly, cytosolic inclusions containing PrPC were identified exclusively in a subpopulation of insulin-producing β-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of β-cells with PrPC inclusions increased with age and was threefold greater in diabetes-prone rats than in controls at 100 days. Cytosolic PrPC expression in β-cells was suppressed whereas the number and size of PrPC inclusions markedly increased in response to hyperglycemia during the first 2 days of continuous glucose infusion in Sprague Dawley rats. In summary, this is the first report describing in vivo cytosolic PrPC aggregation. These unique PrPC inclusions were β-cell specific, more frequent in diabetes-prone animals, and responded to hyperglycemia in glucose-infused Sprague Dawley rats. These data suggest a potential dysfunction in β-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis. © 2007 USCAP, Inc All rights reserved.