Pronounced cytosolic aggregation of cellular prion protein in pancreatic beta-cells in response to hyperglycemia.
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 beta-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 beta-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of beta-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 beta-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 beta-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 beta-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis.
Strom
Alexander
A
Molecular Medicine, Ottawa Health Research Institute, Ottawa, ON, Canada.
Wang
Gen-Sheng
GS
Reimer
Rudolph
R
Finegood
Diane T
DT
Scott
Fraser W
FW
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D018621:PrPC Proteins / Q000378:metabolism*; D051381:Rats; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley
D018621:PrPC Proteins; D005947:Glucose