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by Keyword: Prion Protein


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Matamoros-Angles, A., Gayosso, L. M., Richaud-Patin, Y., Di Domenico, A., Vergara, C., Hervera, A., Sousa, A., Fernández-Borges, N., Consiglio, A., Gavín, R., López de Maturana, R., Ferrer, I., López de Munain, A., Raya, A., Castilla, J., Sánchez-Pernaute, R., Del Río, J. A., (2017). iPS cell cultures from a Gerstmann-Sträussler-Scheinker patient with the Y218N PRNP mutation recapitulate tau pathology Molecular Neurobiology online

Gerstmann-Sträussler-Scheinker (GSS) syndrome is a fatal autosomal dominant neurodegenerative prionopathy clinically characterized by ataxia, spastic paraparesis, extrapyramidal signs and dementia. In some GSS familiar cases carrying point mutations in the PRNP gene, patients also showed comorbid tauopathy leading to mixed pathologies. In this study we developed an induced pluripotent stem (iPS) cell model derived from fibroblasts of a GSS patient harboring the Y218N PRNP mutation, as well as an age-matched healthy control. This particular PRNP mutation is unique with very few described cases. One of the cases presented neurofibrillary degeneration with relevant Tau hyperphosphorylation. Y218N iPS-derived cultures showed relevant astrogliosis, increased phospho-Tau, altered microtubule-associated transport and cell death. However, they failed to generate proteinase K-resistant prion. In this study we set out to test, for the first time, whether iPS cell-derived neurons could be used to investigate the appearance of disease-related phenotypes (i.e, tauopathy) identified in the GSS patient.

Keywords: Cellular prion protein, Gerstmann-Sträussler-Scheinker, Induced pluripotent stem cells, Tau


Vilches, S., Vergara, C., Nicolás, O., Mata, A., Del Río, J. A., Gavín, R., (2016). Domain-specific activation of death-associated intracellular signalling cascades by the cellular prion protein in neuroblastoma cells Molecular Neurobiology 53, (7), 4438–4448

The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrPC) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrPC deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrPC N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrPC deleted forms. Results indicate that PrPC N-terminal deleted forms were properly processed through the secretory pathway. However, PrP

Keywords: Cellular prion protein, Neurotoxicity, Truncated prion protein


Vergara, C., Ordóñez-Gutiérrez, L., Wandosell, F., Ferrer, I., del Río, J. A., Gavín, R., (2015). Role of PrPC expression in tau protein levels and phosphorylation in alzheimer's disease evolution Molecular Neurobiology 51, (3), 1206-1220

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic β-amyloid peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aβ oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrPC) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aβ are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrPC expression in the development of AD, and a putative relationship between PrPC and tau processing is emerging. However, the role of tau/PrPC interaction in AD is poorly understood. In this study, we show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrPC knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrPC expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrPC in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.

Keywords: Aβ oligomers, Alzheimer's disease, Cellular prion protein, Microtubule-associated protein tau


Llorens, Franc, Zafar, Saima, Ansoleaga, Belén, Shafiq, Mohsin, Blanco, Rosi, Carmona, Marga, Grau-Rivera, Oriol, Nos, Carlos, Gelpí, Ellen, del Río, José Antonio, Zerr, Inga, Ferrer, Isidre, (2015). Subtype and regional regulation of prion biomarkers in sporadic Creutzfeldt-Jakob disease Neuropathology and Applied Neurobiology 41, (5), 631-645

Aims Creutzfeldt-Jakob disease (CJD) is a rapid progressive neurological disease leading to dementia and death. Prion biomarkers are altered in the cerebrospinal fluid (CSF) of CJD patients, but the pathogenic mechanisms underlying these alterations are still unknown. The present study examined prion biomarker levels in the brain and CSF of sporadic CJD (sCJD) cases and their correlation with neuropathological lesion profiles. Methods The expression levels of 14-3-3, Tau, phospho-Tau and α-synuclein were measured in the CSF and brain of sCJD cases in a subtype- and region-specific manner. In addition, the activity of prion biomarker kinases, the expression levels of CJD hallmarks and the most frequent neuropathological sCJD findings were analysed. Results Prion biomarkers levels were increased in the CSF of sCJD patients; however, correlations between mRNA, total protein and their phosphorylated forms in brain were different. The observed downregulation of the main Tau kinase, GSK3, in sCJD brain samples may help to explain the differential phospho-Tau/Tau ratios between sCJD and other dementias in the CSF. Importantly, CSF biomarkers levels do not necessarily correlate with sCJD neuropathological findings. Interpretation Present findings indicate that prion biomarkers levels in sCJD tissues and their release into the CSF are differentially regulated following specific modulated responses, and suggest a functional role for these proteins in sCJD pathogenesis.

Keywords: Creutzfeldt-Jakob disease, Prion Protein, Cerebrospinal fluid, Prion Biomarkers, disease subtype, Glycogen synthase kinase 3


Llorens, F., Carulla, P., Villa, A., Torres, J. M., Fortes, P., Ferrer, I., Del Río, J. A., (2013). PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells Journal of Neurochemistry 127, (1), 124-138

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrPSC) has been studied in depth, the physiological role of PrPC remains elusive and controversial. PrPC 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 PrPC in animals and in cellular models. In this article, we present PrPC-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. PrPC over-expression enhances cell proliferation and cell cycle re-entrance after serum stimulation, while PrPC silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrPC in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrPC in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrPC over-expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT-Cdc42-N-WASP-dependent pathway.

Keywords: Cell signaling, Cellular prion protein, Filopodia, Gene expression, Microarray, Proliferation


Llorens, F., Del Rio, J. A., (2012). Unraveling the neuroprotective mechanisms of PrPC in excitotoxicity Prion 6, (3), 245-251

Knowledge of the natural roles of cellular prion protein (PrPC) is essential to an understanding of the molecular basis of prion pathologies. This GPIanchored protein has been described in synaptic contacts, and loss of its synaptic function in complex systems may contribute to the synaptic loss and neuronal degeneration observed in prionopathy. In addition, Prnp knockout mice show enhanced susceptibility to several excitotoxic insults, GABAA receptor-mediated fast inhibition was weakened, LTP was modified and cellular stress increased. Although little is known about how PrPC exerts its function at the synapse or the downstream events leading to PrPCmediated neuroprotection against excitotoxic insults, PrPC has recently been reported to interact with two glutamate receptor subunits (NR2D and GluR6/7). In both cases the presence of PrPC blocks the neurotoxicity induced by NMDA and Kainate respectively. Furthermore, signals for seizure and neuronal cell death in response to Kainate in Prnp knockout mouse are associated with JNK3 activity, through enhancing the interaction of GluR6 with PSD-95. In combination with previous data, these results shed light on the molecular mechanisms behind the role of PrPC in excitotoxicity. Future experimental approaches are suggested and discussed.

Keywords: Prion protein, Excitotoxicity, Neuroprotection, Glutamate receptors, Synapse, prionopathy


Carulla, Patricia, Bribian, Ana, Rangel, Alejandra, Gavin, Rosalina, Ferrer, Isidro, Caelles, Carme, Antonio del Rio, Jose, Llorens, Franc, (2011). Neuroprotective role of PrP(C) against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding Molecular Biology of the Cell 22, (17), 3041-3054

Cellular prion protein (PrP(C)) is a glycosyl-phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP(SC)) induces transmissible spongiform encephalopathies. In contrast, PrP(C) has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP(C) in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP(C) has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)-mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnp(%) Jnk3(%) mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP(C)-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP(C) with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6-PSD-95 interaction after KA injections was favored by the absence of PrP(C). Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrP(C) against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

Keywords: Ischemic brain-injury, Prion protein PrP(C), Stress-inducible protein-1, Synaptic plasticity, Neurite outgrowth, Signaling module, Caspase-3 activation, Organotypic cultures, Cerebral-ischemia


Rangel, A., Madroñal, N., Gruart i Massó, A., Gavin,, Llorens, Sumoy, Torres, Delgado-Gar, Del Rio, J. A., (2009). Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice PLoS ONE 4, (10), e7592 (1-14)

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrPsc) of the natural cellular prion protein (PrPc) encoded by the Prnp gene. Although several roles have been attributed to PrPc, its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrPc studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Methodology/Principal Findings: Here we explore the role of PrPc expression in neurotransmission and neural excitability using wild-type, Prnp 2/2 and PrPc-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp 2/2 mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using IlluminaTM microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp 2/2 and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABAA and AMPA-kainate receptors are co-regulated in both Prnp 2/2 and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABAA and AMPA-Kainate neurotransmission. New PrPc functions have recently been described, which point to PrPc as a target for putative therapies in Alzheimer’s disease. However, our results indicate that a ‘‘gain of function’’ strategy in Alzheimer’s disease, or a ‘‘loss of function’’ in prionopathies, may impair PrPc function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Keywords: Prions, Prionopathies, Natural cellular prion protein (PrPc), Hippocampus, GABA (A) receptor, Glutamate Receptor


Bravo, R., Arimon, M., Valle-Delgado, J. J., Garcia, R., Durany, N., Castel, S., Cruz, M., Ventura, S., Fernàndez-Busquets, X., (2008). Sulfated polysaccharides promote the assembly of amyloid beta(1-42) peptide into stable fibrils of reduced cytotoxicity Journal of Biological Chemistry 283, (47), 32471-32483

The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid beta peptide (A beta) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, A beta(1-42). Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant beta-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for A beta(1-42) fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different A beta(1-42) species on Ca2+ homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca2+ that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca2+ increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.

Keywords: AFM, Alzheimers-disease, Chondroitin sulfate, Heparan-sulfate, Lipid-bilayers, Beta-peptide, In-vitro, Neurodegenerative diseases, Extracellular-matrix, Prion protein


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