We previously demonstrated that the expression of cellular prion protein (PrPC) in islet [beta]-cells is suppressed in hyperglycemic rats suggesting a major role for PrPC in blood glucose regulation. To further characterize the function of PrPC in glucose homeostasis, we studied glucoregulation in PrPC knockout (PrPC KO) mice.
Glucose tolerance, insulin secretion, and insulin sensitivity were analyzed to assess glucoregulation in Zrch I PrPC KO and the C57BL/6 (control) mice. Immunohistochemistry and morphometry were used to measure [beta]-cell mass.
Male PrPC KO mice had significantly increased blood glucose concentration 60, 120, and 180 minutes after intraperitoneal injection of glucose compared with C57BL/6 mice. Female PrPC KO mice showed a less pronounced phenotype of glucose intolerance. Evaluation of [beta]-cell mass, insulin and proinsulin deficiency, and insulin resistance in male mice revealed essentially no difference between PrPC KO and control mice. The only exception was an increase in serum insulin concentration in male PrPC KO mice 5 minutes after glucose injection.
This report is the first to show that PrPC in [beta]-cells is involved in glucoregulation. A further understanding of the role of PrPC in regulating [beta]-cell function will provide valuable insight into the mechanisms of blood glucose regulation.
[Show abstract][Hide abstract] ABSTRACT: The cellular prion protein (PrP(C)) plays a key role in prion diseases when it converts to the pathogenic form scrapie prion protein. Increasing knowledge of its participation in prion infection contrasts with the elusive and controversial data regarding its physiological role probably related to its pleiotropy, cell-specific functions, and cellular-specific milieu. Multiple approaches have been made to the increasing understanding of the molecular mechanisms and cellular functions modulated by PrP(C) at the transcriptomic and proteomic levels. Gene expression analyses have been made in several mouse and cellular models with regulated expression of PrP(C) resulting in PrP(C) ablation or PrP(C) overexpression. These analyses support previous functional data and have yielded clues about new potential functions. However, experiments on animal models have shown moderate and varied results which are difficult to interpret. Moreover, studies in cell cultures correlate little with in vivo counterparts. Yet, both animal and cell models have provided some insights on how to proceed in the future by using more refined methods and selected functional experiments.
[Show abstract][Hide abstract] ABSTRACT: Prnp(-/-) mice lack the prion protein PrP(C) and are resistant to prion infections, but variable phenotypes have been reported in Prnp(-/-) mice and the physiological function of PrP(C) remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp(-/-) mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrP(C) is instead controlled by a linked locus encoding the signal regulatory protein α (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrP(C) suggests that additional phenotypes reported in Prnp(-/-) mice may actually relate to Sirpa or other genetic confounders.
Journal of Experimental Medicine 10/2013; 210(12). DOI:10.1084/jem.20131274 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deletion of cellular isoform of prion protein (PrP C) increases neuronal predisposition to damage by modulating apoptosis and the negative consequences of oxidative stress. In vivo studies have demonstrated that PrP C -deficient mice are more prone to seizure, depression, and induction of epilepsy and experience extensive cerebral damage following ischemic challenge or viral infection. In addition, adenovirus-mediated overexpression of PrP C reduces brain damage in rat models of cerebral ischemia. In experimental autoimmune encephalomyelitis, PrP C -deficient mice reportedly have a more aggressive disease onset and less clinical improvement during the chronic phase than wild-type mice mice. In mice given oral dextran sulfate, PrP C has a potential protective role against inflammatory bowel disease. PrP C -deficient mice demonstrate significantly greater increases in blood glucose concentrations after intraperitoneal injection of glucose than wild-type mice. Further in vivo challenges to PrP gene-deficient models and conditional knockout models with siRNA and in vivo administration of PrP-ligating agents may assist in refining knowledge of the lymphoid function of PrP C and predicting the effects of anti-PrP treatment on the immune system. Together, these findings indicate that PrP C may have multiple neuroprotective and anti-inflammatory roles, which explains why this protein is so widely expressed.
Microbiology and Immunology 07/2014; 58(7):361-374. DOI:10.1111/1348-0421.12162 · 1.24 Impact Factor
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