Is indeed the prion protein a Harlequin servant of "many" masters?

Sorgato, Maria Catia; Peggion, Caterina; Bertoli, Alessandro

doi:10.4161/pri.3.4.10012

Cited by 24 publications

(22 citation statements)

References 59 publications

(74 reference statements)

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“…Human PrP C is an abundantly expressed 209-residue glycoprotein, which largely localizes to cholesterolrich lipid rafts on the outer surface of the cell membrane via a C-terminal glycophosphatidylinositol anchor (18). Although the protein is best known for its role, in a misfolded state, as a pathogenic agent in prion diseases (18 -21), it appears to have a range of normal physiological functions (22)(23)(24), playing a role in copper homeostasis, cellular signaling, neuroprotection, cell adhesion, and synaptogenesis. Using an unbiased proteomewide screen, Lauren et al (17) recently found that cell surface PrP C acts as a highly specific binding site for synthetic A␤42 oligomers.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Interaction between Human Prion Protein and Amyloid-β (Aβ) Oligomers

Chen

Yadav

Surewicz

2010

Journal of Biological Chemistry

247

291

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Soluble oligomers of A␤42 peptide are believed to play a major role in the pathogenesis of Alzheimer disease (AD). It was recently found that at least some of the neurotoxic effects of these oligomers may be mediated by specific binding to the prion protein, PrP C , on the cell surface (Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., and Strittmatter, S. M. (2009) Nature 457, 1128 -1132). Here we characterized the interaction between synthetic A␤42 oligomers and the recombinant human prion protein (PrP) using two biophysical techniques: site-directed spin labeling and surface plasmon resonance. Our data indicate that this binding is highly specific for a particular conformation adopted by the peptide in soluble oligomeric species. The binding appears to be essentially identical for the Met 129 and Val 129 polymorphic forms of human PrP, suggesting that the role of PrP codon 129 polymorphism as a risk factor in AD is due to factors unrelated to the interaction with A␤ oligomers. It was also found that in addition to the previously identified ϳ95-110 segment, the second region of critical importance for the interaction with A␤42 oligomers is a cluster of basic residues at the extreme N terminus of PrP (residues 23-27). The deletion of any of these segments results in a major loss of the binding function, indicating that these two regions likely act in concert to provide a high affinity binding site for A␤42 oligomers. This insight may help explain the interplay between the postulated protective and pathogenic roles of PrP in AD and may contribute to the development of novel therapeutic strategies as well. Alzheimer disease (AD)2 is a devastating age-related neurodegenerative disorder leading to memory loss and progressive decline in cognitive ability (1-3). Pathologically, the disease is characterized by the formation of neurofibrillary tangles composed of hyperphosphorylated Tau and accumulation of extracellular amyloid plaques (1-6). The main component of these plagues is the 40 -42-amino acid residue amyloid-␤ (A␤) peptide, a product of proteolytic processing of a large membrane glycoprotein, amyloid precursor protein (APP).Although the etiology of AD remains poorly understood, the leading hypothesis is that the major causative agent is the aggregated form of A␤ (4, 7). Although in the past much attention has focused on mature ␤-sheet-rich amyloid fibrils, more recent evidence points to a critical role of smaller, soluble A␤ oligomers (8 -13). In contrast to poor quantitative correlation between the burden of insoluble fibrillar amyloid plagues and the degree of dementia, the severity of AD appears to correlate well with the concentration of soluble A␤ oligomers (9 -11). Furthermore, these soluble oligomers have been shown to be potent neurotoxins in vitro and in vivo; among other effects, they were reported to inhibit hippocampal long term potentiation, a widely used electrophysiological measure of synaptic plasticity related to learning and memory, and cause impairment of long term memory in rats (...

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Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Interaction between Human Prion Protein and Amyloid-β (Aβ) Oligomers

Chen

Yadav

Surewicz

2010

Journal of Biological Chemistry

247

291

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“…11 Our data intimately relate to this issue, by supporting the proposition that PrP C participates in transducing signals that eventually regulate the cell phosphorylation cascades. 26 However, having identified TNFα as precocious actor of PrP C -mediated signals, they also raise the hypothesis that PrP C could modulate the activity of enzymes that release signaling molecules, as is TNFα.…”

Section: Prp C As Regulator Of Extracellular Matrix Proteasesmentioning

confidence: 99%

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

Stella

Massimino²,

Sorgato

et al. 2010

Cell Cycle

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“…Importantly, the same holds true when the expression of PrP C is postnatally abrogated (40). The extensive search for PrP C 's raison d'être has ascribed to the protein a plethora of functions (for updated reviews, see references 1 and 35); among these, roles in cell adhesion, migration, and differentiation have been proposed whereby PrP C could act by modulating different cell-signaling pathways (63). In this framework, a variety of neuronal proteins have been hypothesized to interact with PrP C (reviewed in references 1 and 11), for example, cell adhesion molecules or extracellular matrix proteins, which could explain the capacity of PrP C to mediate the neuritogenesis and neuronal differentiation observed in several cell model systems (13,22,23,27,36,59,64).…”

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confidence: 99%

Cellular Prion Protein Promotes Regeneration of Adult Muscle Tissue

Stella¹,

Massimino

Sandri

et al. 2010

Molecular and Cellular Biology

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It is now well established that the conversion of the cellular prion protein, PrP C , into its anomalous conformer, PrP Sc , is central to the onset of prion disease. However, both the mechanism of prion-related neurodegeneration and the physiologic role of PrP C are still unknown. The use of animal and cell models has suggested a number of putative functions for the protein, including cell signaling, adhesion, proliferation, and differentiation. Given that skeletal muscles express significant amounts of PrP C and have been related to PrP C pathophysiology, in the present study, we used skeletal muscles to analyze whether the protein plays a role in adult morphogenesis. We employed an in vivo paradigm that allowed us to compare the regeneration of acutely damaged hind-limb tibialis anterior muscles of mice expressing, or not expressing, PrP C . Using morphometric and biochemical parameters, we provide compelling evidence that the absence of PrP C significantly slows the regeneration process compared to wild-type muscles by attenuating the stress-activated p38 pathway, and the consequent exit from the cell cycle, of myogenic precursor cells. Demonstrating the specificity of this finding, restoring PrP C expression completely rescued the muscle phenotype evidenced in the absence of PrP C .

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Is indeed the prion protein a Harlequin servant of "many" masters?

Cited by 24 publications

References 59 publications

Interaction between Human Prion Protein and Amyloid-β (Aβ) Oligomers

Interaction between Human Prion Protein and Amyloid-β (Aβ) Oligomers

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

Cellular Prion Protein Promotes Regeneration of Adult Muscle Tissue

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