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. 2015 May 15;8(5):8042–8050.

Cellular prion protein (PrPC) and its role in stress responses

Liang Zeng 1, Wenquan Zou 2,3, Gongxian Wang 3
PMCID: PMC4509314  PMID: 26221369

Abstract

Investigation of the physiological function of cellular prion protein (PrPC) has been developed by the generation of transgenic mice, however, the pathological mechanisms related to PrPC in prion diseases such as transmissible spongiform encephalopathies (TSEs) are still abstruse. Regardless of some differences, most studies describe the neuroprotective role of PrPC in environmental stresses. In this review, we will update the current knowledge on the responses of PrPC to various stresses, especially those correlated with cell signaling and neural degeneration, including ischemia, oxidative stress, inflammation and autophagy.

Keywords: PrPC, stress response, ischemia, oxidative stress, autophagy, inflammation, cell survival, TSE

Introduction

Transmissible spongiform encephalopathies (TSEs), which include Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straüssler-Scheinker syndrome (GSS) in humans [1-3], scrapie in sheep and goat [4], Bovine spongiform encephalopathy (BSE) in cattle and chronic waste disease (CWD) in deer [5], are a group of transmissible neurodegenerative disorders which advanced by the conformational transition of the host-protein cellular prion (PrPC) into a β-sheet enriched and protease-K-resistant pathological form (PrPSc) [6]. Although the role of PrPSc in the prion disease has been revealed gradually, the physiological function of its isoform, PrPC, still remains elusive.

PrPC, encoded by the PRNP gene [7], is an extracellular protein which is expressed noticeably in neurons of the brain and spinal cord [8]. It is enriched in α-helix domains and anchored to the cell surface by a glycosylphosphatidylinositol (GPI)-link [9]. Many studies demonstrate the neuroprotective role of PrPC and this physiological function is studied by generating various transgenic animal models, such as PrPC knockout mice and PrPC overexpression mice. Different signal pathways, confirmed by numerous studies, are involved in the neuroprotective function of PrPC, including Fyn, cAMP/PKA [10], and phosphorylation of extracellular signal-regulated kinase (ERK1/2) [11]and Akt [12]. In addition, caspase-3 [13] and STAT-1 [14] also are demonstrated as major modulators between PrPC and cell survival.

It is known that PrPC is a copper-binding protein. And the expression level of PrPC seems to correlate with the activities of Cu/Zn superoxide dismutase or glutathione reductase [15]. In the human trophoblast (HTR) cells culture, Copper and hypoxia can upregulate PrPC expression which protects cells against Cu accumulation, Cu-induced production of reactive oxygen species, and trophoblast death [16]. Additionally, a noticed reduction in copper binding to the protein and an increase in blood manganese in the early stages of disease are observed in the brains of scrapie-infected mice [17], suggesting that copper imbalance is an early change in prion disease.

In this paper, we will update the current knowledge about the responses of PrPC to various environmental stresses, especially those correlated with cell signaling and neural degeneration, such as ischemia, oxidative stress, autophagy and inflammation. In addition, we will discuss the feasibility that develops PrPC as a pharmacological intervention in neurodegenerations.

PrPC and Ischemia

The mouse middle cerebral artery occlusion (MCAO) by using the intraluminal filament technique is usually applied for a cerebral ischemia model to study the neuroprotective role of PrPC. By this means, An early upregulation of cellular prion protein (PrPC) after focal cerebral ischemia was observed [18]. The clinical data shows that Patients in acute phase of ischemic stroke had increased plasma levels of circulating PrPC, and the upregulation of PrPC was found in the soma of peri-infarcted neurons as well as in the endothelial cells (EC) of micro-vessels and inflammatory cells in peri-infarcted brain tissue from patients who survived for 2-34 days after an initial stroke. Also, the same pattern was repeated after MCAO of mice in this study [19]. So it is noticeable that PrPC performs a rapid response to ischemia, but the understanding of its function against ischemia remains unclear until the application of PrPC knockout mice. In surprise, after brain ischemic insult, PrPC knockout mice had dramatically increased infarct volumes and decreased behavioral performance [20], manifesting a neuroprotective role of PrPC. In the same model, increased activities of Erk-1/-2, STAT-1 and caspase-3 are observed, indicating the mechanisms underlying PrPC silence- induced injury [14]. Interestingly, PrPC overexpression by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrPC-Flag into ischemic brain, is reported to improve the neurological behavior and reduce the volume of cerebral infarction in rats [21]. However, the role of cellular prion protein in PrPC overexpression mice remains incomplete understood.

It has been widely accepted that PrPC plays a neuroprotective role in an early cerebral ischemic injury through specific pathway. Extracellular signal regulated kinases 1 and 2 (Erk1/2), as an important pathway known to exacerbate ischemia injury, is introduced to identify the effects of PrPC regulation on ischemic cell death. Increased Erk1/2 activation is response to aggravated ischemic brain injury after PrPC deletion in vivo [14]. Correspondingly, significantly smaller infarct volumes and Reduced early postischemic Erk1/2 phosphorylation were observed in PrPC overexpression mice [22], suggesting that Erk1/2 is a cytosolic signaling pathway underlying the neuroprotective effect of PrPC against ischemia. Similarly, the study on another signaling pathway, Akt, produced that the phosphorylation of it contributes to exacerbation of ischemic brain injury in PrPC knockout mice [23]. In contrast, PrPC overexpression did not change postischemic Akt phosphorylation, which acts anti-apoptotic and show reduction in PrPC knockout mice [22]. And, the relevant fluctuations of caspase-3 activation were referred to as a modulation of programmed cell death pathway in above studies.

As a proposed extracellular ligand for PrPC [24], Stress-inducible protein-1 (STI-1) is a novel mechanism involved in the interaction between PrPC and Cerebral Ischemia. STI-1 was upregulated in the ischemic brains of humans and rodents, which can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, promoting bone marrow derived cells (BMDCs) proliferation and migration in vitro as well as recruitment to the ischemic brain in vivo, and augmenting its signaling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain [25]. Other study shows that several Hsp90 client proteins are decreased by 50% in the absence of embryonic STI1. And, increased caspase-3 activation and 50% impairment in cellular proliferation are observed in Mutant STI1 mice, revealing increased vulnerability to ischemic insult [26]. That is, extracellular STI1 prevented ischemia-mediated neuronal death in a prion protein-dependent way.

Besides itself, PrPC also shows protective role against ischemia by its catabolites. In a pressure-induced ischemia model of the rat retina, it is reported that the alpha-secretase-derived N-terminal product of PrPC (N1) inhibits staurosporine-induced caspase-3 activation by modulating P53 transcription and activity [27]. other studies indicate that amyloid-β oligomers (Aβ), hallmark of the Alzheimer disease [28], are bound by N1 which strongly suppresses the neurotoxicity of Aβ in vivo and in vitro [29,30], and this binding depends on the integrity of lipid rafts and the transmembrane lipoprotein receptor-related protein-1 (LRP1) [31].

The above studies suggest a protective role and therapeutic potential of PrPC in cerebral ischemia stress. However, as far as concerned, the clinical application of PrPC against ischemia is still far from us.

PrPC and oxidative stress

Oxidative stress is highly connected with several neurodegenerative disorders, such as CJD [32] and TSEs [33], which were mainly caused by conformation transition of PrPC. In the brain of animal models, Various cellular pathways have been confirmed to participate in the process of oxidative stress in neurodegeneration, including dysfunction of mitochondrial [34], increase of reactive oxygen species (ROS) [35], defects in Cu/Zn superoxide dismutase (SOD) [36,37], and variations in metal metabolism [38]. Recently, in the mouse optic model, the investigation in oxidative stress-associated neurodegeneration shows some inspirations of the therapy by metal chelation treatment: Metal chelator ethylenediaminetetraacetic acid combined with the permeability enhancer methylsulfonylmethane (EDTA-MSM), which can ameliorate sequelae of intraocular pressure(IOP)-induced toxicity without affecting IOP [39].

The protective role of PrPC against oxidative stress has been suggested by several lines of evidence. The study in PrPC knockout mice elucidates that in neurocyte culture, PrPC knockouts are more susceptible to treatments with oxidative stress agents [40], such as metal ions and hydrogen peroxide. Ischemia, as another powerful producer of oxidative stress, also was introduced to reinforce this point of view: Increased infarction area, correlated with oxidative stress, was observed in PrPC knockout mice than wild type mice [34], as mentioned previously.

Though controversies might exist in the mechanism by which PrPC performs its cellular protective function against oxidative stress, it was still mainly accepted that PrPC could detoxify reactive oxygen species (ROS) directly and indirectly [41]. To prove this point, Cu/Zn superoxide dismutase (SOD), one of the major enzymes against cellular oxidative damage was introduced in. As copper-binding protein, PrPC is beyond all doubt correlated with this. The activity of SOD decreased dramatically in PrPC knockout mice which is responsible for larger lesion caused by oxidative stress [42], whereas in PrPC overexpression mice, increased activity of SOD that may be related with copper ions is observed [43].

Defects in copper metabolism also were connected to many neurodegenerative disorders [44]. As a copper-binding protein, PrPC displays its neuroprotective properties like a SOD through chelating copper by a particular section in the N terminal tail of PrPC, composed of octapeptide repeats [45]. Another study shows that the SOD activity induced by PrPC will vanish due to excising octapeptide repeats region from the N terminal region of PrPC [46]. Emerging studies indicate that octapeptide repeats region has an influence on the function of mitochondrial [47]. Once copper cannot bind PrPC properly owing to the lack of this region, dysfunction of mitochondrial arises from reduced activity of cytochrome coxdise, resulting in the production of ROS which activates mitochondria-mediated apoptotic neurodegeneration reversely [48], also suggesting a protective role of PrPC in anti-oxidative stress. And, it is encouraging to see that many efforts are on the way to comprehending the relations between mitochondrial, oxidative stress in neurodegeneration [49,50].

PrPC and Inflammation

Inflammation can induce oxidative stress and antigen-antibody reaction, leading to cellular damage. Sustained brain inflammation is regarded as the main pathogenic process leading to neuronal dysfunction and loss, which, in turn, leads to clinical symptoms in prion disease [51]. Some results demonstrate that targeting of inflammatory glia cytokine pathways, such as formyl peptide receptors (FPR), can suppress Aβ-induced neuroinflammation in vivo, inducing the attenuation of neuronal damage [52]. Thus, a better understanding of drivers in inflammation may well contribute to the development of therapeutic intervention of prion diseases [53].

As a glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface, PrPC is assumed as a protein modulating phagocytosis and inflammatory response. Perhaps the most convincing observation comes from the study on the function of PrPC in the phagocytosis of apoptotic cells, such as macrophages. In vivo studies of acute peritonitis demonstrate that PrPC knockout mice emerge more efficient phagocytosis than wild-type mice and macrophages from PrPC knockout mice present higher rates of phagocytosis than wild-type macrophages in vitro assays. In addition, the deletion of GPI-anchored proteins from the cell surface of macrophages from wild-type mice rendered these cells as efficient as macrophages derived from PrPC knockout mice [54]. Therefore, the demand for understanding the PrPC trafficking in macrophages is increased accordingly. Studies in Ana-1 macrophage cell culture indicate that PrPC present in extracellular space might be externalized through secreted exosomes from macrophages in which Hsp70 may act as a mediator [55].

On the top of this, in neutrophils, another cell type critically involved in both acute and chronic inflammation, the transcription and translation of PrPC can be induced by systemic injection of lipopolysaccharide (LPS). Up-regulation of PrPC was dependent on the serum content of TGF-β and glucocorticoids (GC), which, in turn, are contingent on the activation of the hypothalamic-pituitary-adrenal axis in response to inflammation. In neutrophils, either individually or in combination, GC and TGF-β directly up-regulated PrPC, presenting increased peroxide-dependent cytotoxicity to endothelial cells [56].

Other studies reveal that PrPC can protect from inflammatory pain [57], and Absence PrPC exacerbates and prolongs neuroinflammation in neural system of murine model [58]. Besides in brain [59], the protective role of PrPC against inflammation is observed somewhere else, such as in the gut (colon), reports elucidate that PrPC has a previously unrecognized cytoprotective and anti-inflammatory function by evaluating the course of dextran sodium sulfate (DSS)-induced colitis in different type mice models, including PrPC overexpression and knockout mice [60].

Nevertheless, the theory that PrPC is involved in modulation of phagocytosis of apoptotic cells faces enormous challenges in latest years. After examining a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, researchers found that the regulation of phagocytosis previously ascribed to PrPC is instead controlled by a linked locus encoding the signal regulatory protein α (Sirpa), suggesting that additional phenotypes reported in PrPC knockout mice may actually relate to Sirpa or other genetic confounders [61]. These findings elucidate that modulation of phagocytosis was previously misattributed to PrPC and indicate the directions for the future research.

PrPC and autophagy

Degradation of organelles and long-lived proteins can be modulated by an intracellular degradation process called autophagy, one of the mechanisms of programmed cell death (PCD) like apoptosis. As main components of autophagy, double-membrane autophagosomes can engulf portions of cytoplasm such as mitochondria then fuse with lysosomes and their contents for degradation [62]. Recent reports show ever-increasing interests in the crucial role for autophagy-related processes [63] in relation to several neurodegenerative disorders [64]. The connection between autophagy and neurodegenerations such as TSE [65] has been established gradually through various studies, including the observation on expression of Scrg1 gene, a potential marker of autophagy [66]. As autophagy induction promotes the clearance of aggregate-prone intracytoplasmic proteins which cause neurodegeneration, such as mutant forms of huntingtin, and plays cytoprotective roles in cell and animal models [67], manipulating autophagy might be a ideal therapeutic benefit of patients with neurodegenerative disorders [68].

At least 20 years ago, neuronal autophagy has been adopted into the study on the formation of giant autophagic vacuoles (AV) in neurons of experimental scrapie in hamsters [69]. Then, the studies in PrPC knockout mice show that ectopic expression of Dpl, the prion protein homologue, can cause progressive cerebellar Purkinje cell death in brain neurons [70] where increased amounts of several autophagy-related molecules, such as the scrapie-responsive gene one (Scrg1), LC3B-II and p62 are observed afterwards [71]. In addition, another study shows that the inhibitor of autophagy, such as reticulon 3 (RTN3), attenuates the clearance of cytosolic prion aggregates in cells [72]. Therefore, it is conceivable that autophagy has a physiological role in prion infection. For further understanding of this, Various interventions provoking autophagy are introduced in the study aiming to attenuate the neurotoxicity mediated by prion protein, including imatinib [73,74] and lithium [75] reported previously. And this methodology is duplicated by employing different agents such as melatonin [76], resveratrol [77] and Sirtuin 1 (Sirt1) [78] in recent studies, suggesting that induction of autophagy is beneficial in prion-infected cells and animals [79]. That is, autophagy might serve as a quality controller to restrict the accumulation of misfolded PrP that normally leads to the generation of PrPSc [80].

To investigate whether PrPC is concerned with autophagic degradation machinery, the level of microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker, was ever analyzed by monitoring the conversion from LC3-I into LC3-II in Zürich I Prnp (-/-) hippocampal neuronal cells which is enhanced under the serum deprivation, an inducer of the autophagy [81]. Interestingly, this up-regulation was maintained by the introduction of PrPC into Prnp (-/-) cells but not by the introduction of PrPC lacking octapeptide repeat region, suggesting the octapeptide repeat region of PrPC may play a central role in the modulation of autophagy exhibited by PrPC in neuronal cells. Moreover, another study in glioma cells demonstrates that Silencing of cellular prion protein expression by DNA-antisense oligonucleotides can induce cell death by autophagy, not apoptosis [82].

It is encouraging to see that investigators diversified the relationship between PrPC and Autophagy from different perspectives. For example, Oxidative stress, which is inseparable from PrPC as we mentioned previously is supposed to influence autophagy flux in prion protein-deficient hippocampal cells [83]. And herpes simplex virus 1 (HSV-1) which effectively counteracts autophagy, is also introduced to detail a proautophagic antiviral role for the cellular prion protein [84]. In addition, studies have been processed at a level of ultrastructural organelles such as lipid rafts, into which PrPC interacts with BECN1 to recruit the PIK3C3 complex, and thus activates autophagy in response to Aβ42, elucidating a novel role of PrPC in the regulation of autophagy [85].

Conclusions

In this paper, we have updated the current knowledge on the different responses of PrPC to various environmental stresses, including the increased level of PrPC expression after cerebral ischemia, the PrPC-decreased ROS activities against oxidative stress, PrPC-modulated phagocytosis against inflammation, and the octapeptide repeat region of PrPC modulating autophagy. With the development of neuroprotective mechanisms of PrPC in stresses, modulating environmental stresses via PrPC may be a novel therapeutic approach for neurodegenerative disorders including the prion disease.

Disclosure of conflict of interest

None.

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