The Quest for Cellular Prion Protein Functions in the Aged and Neurodegenerating Brain

Cellular (also termed ‘natural’) prion protein has been extensively studied for many years for its pathogenic role in prionopathies after misfolding. However, neuroprotective properties of the protein have been demonstrated under various scenarios. In this line, the involvement of the cellular prion protein in neurodegenerative diseases other than prionopathies continues to be widely debated by the scientific community. In fact, studies on knock-out mice show a vast range of physiological functions for the protein that can be supported by its ability as a cell surface scaffold protein. In this review, we first summarize the most commonly described roles of cellular prion protein in neuroprotection, including antioxidant and antiapoptotic activities and modulation of glutamate receptors. Second, in light of recently described interaction between cellular prion protein and some amyloid misfolded proteins, we will also discuss the molecular mechanisms potentially involved in protection against neurodegeneration in pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.

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Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0911829107 ◽

2010 ◽

Vol 107 (5) ◽

pp. 2295-2300 ◽

Cited By ~ 314

Author(s):

Claudia Balducci ◽

Marten Beeg ◽

Matteo Stravalaci ◽

Antonio Bastone ◽

Alessandra Sclip ◽

...

Keyword(s):

Cognitive Impairment ◽

Prion Protein ◽

Amyloid Β ◽

Cellular Prion Protein ◽

Long Term Memory ◽

Ample Evidence ◽

Knock Out ◽

Intracerebroventricular Injections ◽

Knock Out Mice

Inability to form new memories is an early clinical sign of Alzheimer’s disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ1–42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ1–42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrPC) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ1–42 oligomers interact with PrPC, with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ1–42 oligomers are responsible for cognitive impairment in AD and that PrPC is not required.

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Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation

Blood ◽

10.1182/blood-2006-03-006759 ◽

2006 ◽

Vol 108 (6) ◽

pp. 2064-2071 ◽

Cited By ~ 82

Author(s):

Gloria Lee ◽

Annie Lo ◽

Sarah A. Short ◽

Tosti J. Mankelow ◽

Frances Spring ◽

...

Keyword(s):

Adhesion Molecule ◽

Molecular Mechanisms ◽

Intercellular Adhesion Molecule ◽

Immunoglobulin Superfamily ◽

Erythroid Progenitors ◽

Island Formation ◽

Knock Out ◽

Erythroblastic Island ◽

Adhesive Interactions ◽

Knock Out Mice

AbstractErythroid progenitors differentiate in erythroblastic islands, bone marrow niches composed of erythroblasts surrounding a central macrophage. Evidence suggests that within islands adhesive interactions regulate erythropoiesis and apoptosis. We are exploring whether erythroid intercellular adhesion molecule 4 (ICAM-4), an immunoglobulin superfamily member, participates in island formation. Earlier, we identified αV integrins as ICAM-4 counterreceptors. Because macrophages express αV, ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knock-out mice and developed quantitative, live cell techniques for harvesting intact islands and for re-forming islands in vitro. We observed a 47% decrease in islands reconstituted from ICAM-4 null marrow compared to wild-type marrow. We also found a striking decrease in islands formed in vivo in knock-out mice. Further, peptides that block ICAM-4/αV adhesion produced a 53% to 57% decrease in reconstituted islands, strongly suggesting that ICAM-4 binding to macrophage αV functions in island integrity. Importantly, we documented that αV integrin is expressed in macrophages isolated from erythroblastic islands. Collectively, these data provide convincing evidence that ICAM-4 is critical in erythroblastic island formation via ICAM-4/αV adhesion and also demonstrate that the novel experimental strategies we developed will be valuable in exploring molecular mechanisms of erythroblastic island formation and their functional role in regulating erythropoiesis.

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A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01441-17 ◽

2017 ◽

Vol 62 (2) ◽

Cited By ~ 6

Author(s):

N. C. Ferreira ◽

L. M. Ascari ◽

A. G. Hughson ◽

G. R. Cavalheiro ◽

C. F. Góes ◽

...

Keyword(s):

Cell Surface ◽

Real Time ◽

Prion Protein ◽

Molecular Mechanisms ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Globular Domain ◽

Mrna Levels ◽

Spongiform Encephalopathies

ABSTRACTThe search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identifiedin vitroto be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPCmRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23–231) as the substrate and PrPScseeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90–231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPCglobular domain. J8 also reduced the fibrillation of mouse rPrP23–231seeded within vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPCon the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPCcontent on the cell surface.

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Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport

PLoS ONE ◽

10.1371/journal.pone.0006115 ◽

2009 ◽

Vol 4 (7) ◽

pp. e6115 ◽

Cited By ~ 55

Author(s):

Ajay Singh ◽

Qingzhong Kong ◽

Xiu Luo ◽

Robert B. Petersen ◽

Howard Meyerson ◽

...

Keyword(s):

Prion Protein ◽

Iron Metabolism ◽

Iron Uptake ◽

Functional Role ◽

Knock Out ◽

Knock Out Mice ◽

Uptake And Transport

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Tissue-Specific Function of Thyroid Hormone Transporters: New Insights from Mouse Models

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1032-8328 ◽

2019 ◽

Vol 128 (06/07) ◽

pp. 423-427 ◽

Cited By ~ 2

Author(s):

Eva Salveridou ◽

Steffen Mayerl ◽

Sivaraj Mohana Sundaram ◽

Boyka Markova ◽

Heike Heuer

Keyword(s):

Thyroid Hormone ◽

Elevated Serum ◽

Transport Processes ◽

Tissue Specific ◽

Knock Out ◽

Serum T3 ◽

A Cell ◽

Knock Out Mice ◽

Mct8 Deficiency ◽

Shed Light

AbstractThyroid hormone (TH) transporters are required for cellular transmembrane passage of TH and are thus mandatory for proper TH metabolism and action. Consequently, inactivating mutations in TH transporters such as MCT8 or OATP1C1 can cause tissue- specific changes in TH homeostasis. As the most prominent example, patients with MCT8 mutations exhibit elevated serum T3 levels, whereas their CNS appear to be in a TH deficient state. Here, we will briefly summarize recent studies of mice lacking Mct8 alone or in combination with the TH transporters Mct10 or Oatp1c1 that shed light on many aspects and pathogenic events underlying global MCT8 deficiency and also underscore the contribution of Mct10 and Oatp1c1 in tissue-specific TH transport processes. Moreover, development of conditional knock-out mice that allow a cell-specific inactivation of TH transporters in distinct tissues, disclosed cell-specific changes in TH signaling, thereby highlighting the pathophysiological significance of local control of TH action.

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Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Blood ◽

10.1182/blood-2011-04-350413 ◽

2012 ◽

Vol 119 (10) ◽

pp. 2422-2429 ◽

Cited By ~ 36

Author(s):

Zhuang Wu ◽

Ming-Cheh Liu ◽

Mei Liang ◽

Jian Fu

Keyword(s):

Particulate Matter ◽

Molecular Mechanisms ◽

Transcriptional Level ◽

Class Iii ◽

Plasminogen Activator Inhibitor 1 ◽

Down Regulation ◽

Knock Out ◽

Fibrin Formation ◽

Knock Out Mice ◽

Particulate Matter Exposure

Abstract Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-κB acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. Our data show that PM exposure led to decreased lung KLF2 and TM expression in wild-type mice, and lung KLF2 and TM protein levels were further decreased in Sirt1 knock-out mice. Importantly, Sirt1 gene delivery inhibited TM and KLF2 down-regulation and reduced lung coagulation after PM exposure. Collectively, our studies indicate that Sirt1 functions as a suppressor of coagulation after particulate matter exposure.

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