Unraveling the neuroprotective mechanisms of PrP<sup>C</sup>in excitotoxicity

Llorens, Franc; Rı́o, José Antonio del

doi:10.4161/pri.19639

Cited by 18 publications

(14 citation statements)

References 107 publications

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“…), PrP C ‐STI1‐mediated neural progenitor/stem cells self‐renewal (Santos et al . ) and GluR6/PSD‐95 interaction, as well as further JNK3 activation in response to kainate (see Llorens and Del Rio for details).…”

Section: Discussionmentioning

confidence: 99%

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PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

Llorens

Carulla

Villa³

et al. 2013

Journal of Neurochemistry

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The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP SC ) has been studied in depth, the physiological role of PrP C remains elusive and controversial.PrP C is a cell-surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP C in animals and in cellular models. In this article, we present PrP C -dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP C overexpression enhances cell proliferation and cell cycle re-entrance after serum stimulation, while PrP C silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP C in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP C in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP C overexpression modulates filopodia formation by Rho GTPase regulation mainly in an AKT-Cdc42-N-WASP-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

“…). Several lines of research point to a role in neuroprotection against a wide range of insults, such as excitotoxicity and serum starvation (Llorens and Del Rio ).…”

mentioning

confidence: 99%

PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

Llorens

Carulla

Villa³

et al. 2013

Journal of Neurochemistry

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“…The physiological role of native PrP C remains unclear. 370 It has been shown that the protein is involved in several cellular processes including neuroprotection against excitotoxicity and serum starvation, 371 proliferation and cell-cell adhesion, 370, 372 formation of synapses 373 and ligand binding. 374, 375 PrP can protect cells against heavy metal overloading and subsequent oxidative stress by binding divalent ions of copper, zinc, manganese and nickel.…”

Section: Prions and Prion Diseasesmentioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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“…Several groups reported in the mid-90s that PrP C -deficiency translates into impairments in LTP (Clinton et al, 1993; Collinge et al, 1994; Manson et al, 1995) and learning and memory. As with polySia-NCAM1, the presence of PrP C has most often been shown to desensitize NMDARs, making them less responsive to low levels of EtOH, NMDA, kainite, or glutamate (Shyu et al, 2005; Rangel et al, 2007; Carulla et al, 2011; Llorens and Del Rio, 2012; Black et al, 2014). This protective role has, however, not remained unchallenged (Herms et al, 1995) and was, for example, not detected when the influence of PrP on LTP was investigated in hippocampal slices dissected from intercrosses of Prnp knockout mice and an AD mouse model, which itself exhibits an LTP defect (Calella et al, 2010).…”

Section: Prp and Polysia-ncam1mentioning

confidence: 99%

NCAM1 Polysialylation

2016

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Much confusion surrounds the physiological function of the cellular prion protein (PrPC). It is, however, anticipated that knowledge of its function will shed light on its contribution to neurodegenerative diseases and suggest ways to interfere with the cellular toxicity central to them. Consequently, efforts to elucidate its function have been all but exhaustive. Building on earlier work that uncovered the evolutionary descent of the prion founder gene from an ancestral ZIP zinc transporter, we recently investigated a possible role of PrPC in a morphogenetic program referred to as epithelial-to-mesenchymal transition (EMT). By capitalizing on PrPC knockout cell clones in a mammalian cell model of EMT and using a comparative proteomics discovery strategy, neural cell adhesion molecule-1 emerged as a protein whose upregulation during EMT was perturbed in PrPC knockout cells. Follow-up work led us to observe that PrPC regulates the polysialylation of the neural cell adhesion molecule NCAM1 in cells undergoing morphogenetic reprogramming. In addition to governing cellular migration, polysialylation modulates several other cellular plasticity programs PrPC has been phenotypically linked to. These include neurogenesis in the subventricular zone, controlled mossy fiber sprouting and trimming in the hippocampal formation, hematopoietic stem cell renewal, myelin repair and maintenance, integrity of the circadian rhythm, and glutamatergic signaling. This review revisits this body of literature and attempts to present it in light of this novel contextual framework. When approached in this manner, a coherent model of PrPC acting as a regulator of polysialylation during specific cell and tissue morphogenesis events comes into focus.

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Unraveling the neuroprotective mechanisms of PrP^Cin excitotoxicity

Cited by 18 publications

References 107 publications

PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

Implications of peptide assemblies in amyloid diseases

NCAM1 Polysialylation

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Unraveling the neuroprotective mechanisms of PrPCin excitotoxicity

Cited by 18 publications

References 107 publications

PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

Implications of peptide assemblies in amyloid diseases

NCAM1 Polysialylation

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Product

Resources

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Unraveling the neuroprotective mechanisms of PrP^Cin excitotoxicity

PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

PrP^C regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells