Academic literature on the topic 'Cellular prion protein physiological function, Myelin'

Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp−/− mice. However, all currently available Prnp−/− lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non–co-isogenic Prnp−/− mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease.

Despite the important role of prion domains in neurodegenerative disease, their physiological function has remained enigmatic. Previous work with yeast prions has defined prion domains as sequences that form self-propagating aggregates. Here, we uncovered an unexpected function of the canonical yeast prion protein Sup35. In stressed conditions, Sup35 formed protective gels via pH-regulated liquid-like phase separation followed by gelation. Phase separation was mediated by the N-terminal prion domain and regulated by the adjacent pH sensor domain. Phase separation promoted yeast cell survival by rescuing the essential Sup35 translation factor from stress-induced damage. Thus, prion-like domains represent conserved environmental stress sensors that facilitate rapid adaptation in unstable environments by modifying protein phase behavior.

Studies on the cellular prion protein (PrPC) have been actively conducted because misfolded PrPC is known to cause transmissible spongiform encephalopathies or prion disease. PrPC is a glycophosphatidylinositol-anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrPC mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrPC regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrPC promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrPC via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody.

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.

Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.

Although the physiological function of the cellular prion protein (PrPC) remains unknown, several evidences support the notion of its role in copper homeostasis. PrPCbinds Cu2+through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+of the adenosine triphosphate (ATP)-evoked currents in the P2X4receptor subtype, highlighting a modulatory role for PrPCin synaptic transmission through regulation of Cu2+levels. Here, we study the effect of full-length PrPCin Cu2+inhibition of P2X4receptor when both are coexpressed. PrPCexpression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4receptors. However, the presence of PrPCreduces the inhibition by Cu2+of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+binding domain. Thus, our observations suggest a role for PrPCin modulating synaptic activity through binding of extracellular Cu2+.

A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.

The cellular form of the prion protein (PrPC) has been widely investigated since its alternative folded isoform is the causative agent of prion disorders. PrPC is highly expressed in the nervous system, where it is involved in many physiological processes such as the maintenance of peripheral nervous system (PNS) myelination. A similar role in the central nervous system (CNS) is still controversial, since PrPC absence affects proliferation and maturation of oligodendrocyte precursor cells without affecting myelination. On the other hand, PrPC is involved in metal homeostasis and modulates oxidative stress, two processes influencing myelin formation and maintenance. In light of these considerations, we took advantage of wild-type (WT, Prnp+/+) and PrPC knock-out (KO, Prnp0/0) mice to investigate PrPC role in CNS myelination. Myelin composition was examined in mouse brains at different developmental stages, from early postnatal days to aging, through cholesterol content measurement and through myelin protein and gene expression evaluation. Furthermore, peripheral myelin status was also investigated in the sciatic nerve (SN) in order to have a comparative analysis between the CNS and PNS myelin. Finally, an ex vivo model based on organotypic hippocampal cultures (OHC) was established to better investigate PrPC role in CNS myelin. Concerning the PNS, most of our results are consistent with the PNS myelin degeneration observed in literature. Accordingly, results show a 50% decrease in SN cholesterol content, a strong reduction of myelin genes transcription and an altered expression level of some myelin proteins during Prnp0/0 mouse aging. Moreover, some changes in the early postnatal period were also detected. Focusing on the CNS, a small reduction in cholesterol content was observed at postnatal day 1 and in aging brains of Prnp0/0 mice, suggesting an alteration in CNS myelin status. Differently from PNS, CNS myelin proteins are slightly upregulated in Prnp0/0 brains during the whole life. In particular, in Prnp0/0 brains a higher amount of myelin proteolipid protein, myelin basic protein, myelin oligodendrocyte glycoprotein and the glycosylated form of myelin associated glycoprotein was detected. This myelin protein upregulation correlates with a higher gene expression in Prnp0/0 mouse brains. To better investigate PrPC role in CNS myelination, an ex vivo model based on OHC was established. In accordance with in vivo experiments, after 28 days in vitro the amount of myelin proteins and myelin gene expression is higher in Prnp0/0 than in Prnp+/+ OHC. Furthermore, the copper chelator cuprizone (CZ) was administered to OHC to investigate its effect in PrPC presence or absence. CZ treatment did not trigger the expected myelin degeneration. Differently it induced an increase in myelin protein percentage particularly in Prnp+/+ OHC, while the effect on Prnp0/0 OHC was milder. Thus, different response of Prnp+/+ and Prnp0/0 OHC to CZ exposure denotes a distinct CNS susceptibility to this kind of stimulus in the presence or absence of PrPC. Altogether, these results support the hypothesis that PrPC is involved in CNS myelination, although in a different manner compared to the PNS. In fact, the differences observed in CNS lipid composition, protein expression and gene transcription are less pronounced compared to PNS, but are extended for the whole lifetime. Since electron microscopy on CNS myelinated regions did not show gross morphological changes between Prnp+/+ and Prnp0/0 mice, it is possible that myelin protein overexpression could be the result of a compensatory mechanism to prevent functional abnormalities. Furthermore, since PrPC plays neuroprotective roles, it is possible that it could protect myelin under stress conditions.

Microglia are important in the regulation of the inflammatory response in regulating the release of proinflammatory mediators in the brain. Through their phagocytic actions, microglia are significant in the CNS when it comes to the body's response to physiological insults by promoting repair of impaired brain function. They do so by engulfing and degrading microbes as well as brain-derived debris and proteins such as myelin and axonal fragments, amyloid-beta, and apoptotic cells. This mitophagic activity of microglia is of importance in neurodegeneration. In most neurodegenerative disorders, mitophagy is impaired with resultant accumulation of dysfunctional mitochondria as well as processes such as lysosomal fusion and autophagosomes. In Parkinson's and Alzheimer's for example, impaired mitophagy accounts for the build-up of α-synuclein and amyloid respectively in affected individuals. The chapter discusses extensively the link between microglia mitophagy and neurodegeration and how dysfunctional mitophagy increases the likelihood of their occurrence.