The Cellular Prion Protein: A Player in Immunological Quiescence

Bakkebø, Maren; Mouillet-Richard, Sophie; Espenes, Arild; Goldmann, Wilfred; Tatzelt, Jörg; Tranulis, Michael A.

doi:10.3389/fimmu.2015.00450

Cited by 43 publications

(39 citation statements)

References 150 publications

(167 reference statements)

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“…In fact, many of the proteins that appear to interact with PrP C may merely be part of the same multiprotein complex or complexes rather than being direct binding partners. Alternatively, the relatively flexible structure of the PrP C N-terminal domain may allow the protein to bind directly to multiple partners (Bakkebo et al, 2015), potentially enabling PrP C to act as a scaffolding protein that mediates the formation of a number of different multiprotein complexes at the cell surface, as has been proposed previously (Linden et al, 2008). …”

Section: Prpc Functionmentioning

confidence: 98%

“…Removal of both signal sequences results in a mature protein of 208 amino acids (residues 23–230 of the precursor protein), the structure of which is shown in Figure 2. The N-terminal domain is traditionally viewed as intrinsically disordered, but may possess elements of stable structure (Gill et al, 2000; Blanch et al, 2004; Taubner et al, 2010) that could enable PrP C to interact with multiple partners (Bakkebo et al, 2015). The N-terminal domain also contains four tandem repeats of a sequence of eight amino acids, a region of PrP C that is missing in Dpl.…”

Section: The Cellular Prion Protein and Its Genementioning

confidence: 99%

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Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.

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Section: Prpc Functionmentioning

confidence: 98%

Section: The Cellular Prion Protein and Its Genementioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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“…It is striking that PrP is highly abundant in organs that possess immunological privilege, such as brain, placenta, and testicles 90 . Fittingly, in several inflammatory processes, such as ischemia, brain trauma, and EAE, the inflammatory damage is exacerbated when PrP is absent, suggesting a role in immune quiescence 90 .…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Extracellular Vesicles are Highly Enriched in the Prion Protein and Its C1 Fragment: Relevance for Cellular Uptake and Implications in Stroke

Brenna

Altmeppen

Mohammadi

et al. 2019

Preprint

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Extracellular vesicles (EVs) are important means of intercellular communication and a potent tool for regenerative therapy. In ischemic stroke, transient blockage of a brain artery leads to a lack of glucose and oxygen in the affected brain tissue, provoking neuronal death by necrosis in the core of the ischemic region. The fate of neurons in the surrounding penumbra depends on the stimuli, including EVs, received during the following hours. A detailed characterization of such stimuli is crucial not only for understanding stroke pathophysiology but also for new therapeutic interventions.In the present study, we characterize the EVs in mouse brain under physiological conditions and 24h after induction of transient ischemia in mice. We show that, in steady-state conditions, microglia are the main source of small EVs (sEVs) whereas after ischemia, the main EV population originates from astrocytes. Moreover, sEVs presented high amounts of the prion protein (PrP) which were increased after stroke. Conspicuously, sEVs were particularly enriched in a truncated PrP fragment (PrP-C1). Because of similarities between PrP-C1 and certain viral surface proteins, we studied the cellular uptake of brain-derived sEVs from mice lacking (PrP-KO) or containing PrP (WT). We show that PrP-KO-EVs are rapidly taken up by neurons and colocalize with lysosomes. Although eventually WT-EVs are also found in lysosomes, the amount taken up by neurons is significantly higher for PrP-KO-EVs. Likewise, microglia and astrocytes were also engulfing PrP-KO-sEVs more efficiently than WT-sEVs.Our results provide information on the relative contribution of brain cell types to the sEV pool in mice and indicate that increased release of sEVs by astrocytes together with elevated levels of PrP in sEVs may play a role in intercellular communication at early stages after stroke. In addition, amounts of PrP (and probably PrP-C1) in brain sEVs seem to contribute to their cellular uptake.

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“…Bound to the plasma membrane by a glycosylphosphatidylinositol anchor, PrP C is dispersed throughout the human body, particularly in the central nervous system, heart, skeletal muscle, intestinal tissue, uterus, and testis [10]. PrP C , which is encoded by the PRNP gene, has been shown to play a significant role in defending tissues against various stresses, including ischemic [11] and inflammatory [12] stresses. In particular, the oxidative stress caused by ischemia, which leads to reactive oxygen species production, DNA damage, and cell apoptosis, can be alleviated by the detoxifying effects of PrP C [13], possibly via the action of its ligand, STI-1, which promotes the migration and proliferation of bone marrow-derived cells to the ischemic brain [14].…”

Section: Introductionmentioning

confidence: 99%

C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

Han

Yun

Lee

et al. 2018

Cell Physiol Biochem

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Background/Aims: Stem cell transplantation has emerged as a promising therapeutic strategy, but the exact mechanisms by which stem cells exposed to hypoxic conditions increase the survival rate and rescue ischemic injury at the graft site are not well known. In this study, we aimed to determine if c-Met-activated mesenchymal stem cells (MSCs) pre-exposed to hypoxia promote therapeutic efficacy when transplanted to ischemic models, and whether c-Met interacts with cellular prion protein (PrP^C) present in the ischemic tissue. Methods: Western blot analysis was performed to determine the expression levels of PrP^C, C-caspase-3, and C-PARP-1, as well as the phosphorylation of Akt, p38, JNK, and BAX. A co-immunoprecipitation assay was performed to show that PrP^C binds with c-Met in vitro. An adhesion assay was performed to explore the alterations in MSCs attached to myoblasts (in vitro), and an invasion assay was performed to determine the effect on MSC invasion capacity upon interaction with myoblast-induced c-Met and PrP^C. CD31-positive capillaries and αSMA-positive arterioles in in vivo hindlimb ischemic tissue were quantified by immunofluorescence staining. The level of apoptosis in the tissue of each group was assessed by quantifying the number of C-caspase-3-positive cells. Finally, laser Doppler technology was utilized to detect the enhanced angiogenic effects in vivo. Results: We showed that hypoxic conditions increased PrP^C levels in vivo (hindlimb ischemic tissue) and in vitro (myoblasts) and increased c-Met levels in MSCs. To identify the relationship between c-Met from MSCs and PrP^C from myoblasts, we used a co-culturing system with myoblasts and MSCs pre-exposed to hypoxia. Hypoxia increased the phosphorylation of mitogen-activated protein kinases. Transplantation of hypoxia-pre-exposed MSCs to the ischemic site increased anti-apoptosis and enhanced the survival and proliferation of transplanted MSCs in a murine hindlimb model, resulting in improved functional recovery of the ischemic tissue. All the aforementioned effects were inhibited by the pretreatment of MSCs with the c-Met-neutralizing antibody Conclusion: c-Met-activated MSCs pre-exposed to hypoxia interact with PrP^C at the site of ischemic injury to increase the efficiency of MSC transplantation. Hence, our study demonstrated that c-Met is a potential target for MSC-based therapies.

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The Cellular Prion Protein: A Player in Immunological Quiescence

Cited by 43 publications

References 150 publications

Physiological Functions of the Cellular Prion Protein

Physiological Functions of the Cellular Prion Protein

Brain-Derived Extracellular Vesicles are Highly Enriched in the Prion Protein and Its C1 Fragment: Relevance for Cellular Uptake and Implications in Stroke

C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

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