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

Abstract

Cellular prion protein (PrP C ), 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 PrP C was altered in islets of Langerhans in a model of spontaneous type 1 diabetes, the diabetes-prone BioBreeding (BBdp) rat and a model of b-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. PrP C was ubiquitously expressed in all four major endocrine cell types within islets. Surprisingly, cytosolic inclusions containing PrP C were identified exclusively in a subpopulation of insulin-producing b-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of b-cells with PrP C inclusions increased with age and was threefold greater in diabetes-prone rats than in controls at 100 days. Cytosolic PrP C expression in b-cells was suppressed whereas the number and size of PrP C 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 PrP C aggregation. These unique PrP C inclusions were b-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 b-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis.

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

“…2,8 For example, nonobese diabetic (NOD) mice and BBdp rats exhibit subtle abnormalities in the target tissue, including increased islet neogenesis, 2,13 increased apoptosis, 14 decreased clearance of apoptotic bodies, 15 abnormal islet morphology 16 and increased aggregation of cellular prion protein in b-cells. 17 Most of these studies focused on islet abnormalities as potential initiators of the b-cell specific autoimmune attack. A key question remains whether islet development per se is abnormal in diabetes-prone individuals.…”

Prions: Beyond a Single Protein

“…Interestingly, cytosolic PrP C aggregates were found in ␤-islet pancreatic cells in diabetesprone rats (78). In rodent models of hypoxic-ischemic injury, somal PrP C aggregates were observed in the penumbra of hypoxic damage (79); moreover, knockout mice devoid of PrP C were more susceptible to strokes, as evidenced by larger infarct sizes than those of wild-type mice (79,80).…”

Insoluble cellular prion protein and its association with prion and Alzheimer diseases

“…13,61 Notably, cytosolic PrP aggregates were also observed in pancreatic beta-cells of uninfected rats in response to hyperglycemia. 62 By differential SDS solubility assay, PrP C species with either lower or higher solubility were also differentiated in the brain homogenates of non-infected humans, sheep and cattle. 63 Although the iPrP C molecule possesses PrP Sc -like physicochemical properties-for instance, insolubility in non-denaturing detergents, a strong tendency to form aggregates and resistance to PK-treatment-it is unclear whether these small amounts PrP C aggregates acquire infectivity in the normal human brain.…”