Staff member

Rosalina Gavín Marín

Senior Researcher
Molecular and Cellular Neurobiotechnology
+34 934 031 185
Staff member publications

Del Río, J. A., Ferrer, Isidre, Gavín, R., (2018). Role of cellular prion protein in interneuronal amyloid transmission Progress in Neurobiology 165-167, 87-102

Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a ‘prion-like’ spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrPC) binding has been a focus of interest in Alzheimer’s disease (AD). At the molecular level, β-amyloid/PrPC interaction takes place in two differently charged clusters of PrPC. In addition to β-amyloid, participation of PrPC in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrPC as a putative receptor for amyloid proteins and the physiological consequences of these interactions..

Keywords: Cellular prion protein, Amyloid, Proteinaceous species, ‘prion-like’ spreading, Spreading, Neurodegeneration

Urrea, L., Segura, Miriam, Masuda-Suzukake, M., Hervera, A., Pedraz, L., Aznar, J. M. G., Vila, M., Samitier, J., Torrents, E., Ferrer, Isidro, Gavín, R., Hagesawa, M., Del Río, J. A., (2018). Involvement of cellular prion protein in α-synuclein transport in neurons Molecular Neurobiology 55, (3), 1847-1860

The cellular prion protein, encoded by the gene Prnp, has been reported to be a receptor of β-amyloid. Their interaction is mandatory for neurotoxic effects of β-amyloid oligomers. In this study, we aimed to explore whether the cellular prion protein participates in the spreading of α-synuclein. Results demonstrate that Prnp expression is not mandatory for α-synuclein spreading. However, although the pathological spreading of α-synuclein can take place in the absence of Prnp, α-synuclein expanded faster in PrPC-overexpressing mice.

Keywords: Amyloid spreading, Microfluidic devices, Prnp, Synuclein

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, Isidro, López de Munain, A., Raya, A., Castilla, J., Sánchez-Pernaute, R., Del Río, J. A., (2018). iPS cell cultures from a Gerstmann-Sträussler-Scheinker patient with the Y218N PRNP mutation recapitulate tau pathology Molecular Neurobiology 55, (4), 3033-3048

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

Mata, Agata, Urrea, Laura, Vilches, Silvia, Llorens, Franc, Thüne, Katrin, Espinosa, Juan-Carlos, Andréoletti, Olivier, Sevillano, Alejandro M., Torres, Juan María, Requena, Jesús Rodríguez, Zerr, Inga, Ferrer, Isidro, Gavín, Rosalina, del Río, José Antonio, (2017). Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies Molecular Neurobiology 54, (8), 6412-6425

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer’s disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.

Keywords: Reelin, Creutzfeldt-Jakob disease, Dab-1, Cellular prion protein

Urrea, Laura, Ferrer, Isidro, Gavín, Rosalina, del Río, José Antonio, (2017). The cellular prion protein (PrPC) as neuronal receptor for α-synuclein Prion 11, (4), 226-233

The term ‘prion-like’ is used to define some misfolded protein species that propagate intercellularly, triggering protein aggregation in recipient cells. For cell binding, both direct plasma membrane interaction and membrane receptors have been described for particular amyloids. In this respect, emerging evidence demonstrates that several β-sheet enriched proteins can bind to the cellular prion protein (PrPC). Among other interactions, the physiological relevance of the binding between β-amyloid and PrPC has been a relevant focus of numerous studies. At the molecular level, published data point to the second charged cluster domain of the PrPC molecule as the relevant binding domain of the β-amyloid/PrPC interaction. In addition to β-amyloid, participation of PrPC in binding α-synuclein, responsible for neurodegenerative synucleopathies, has been reported. Although results indicate relevant participation of PrPC in the spreading of α-synuclein in living mice, the physiological relevance of the interaction remains elusive. In this comment, we focus our attention on summarizing current knowledge of PrPC as a receptor for amyloid proteins and its physiological significance, with particular focus on α-synuclein.

Keywords: α-synuclein, Charged cluster domain, Interneuronal transport, LAG3, Neurodegeneration, PrPC, Parkinson disease

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, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.

Keywords: Cellular prion protein, Neurotoxicity, Truncated prion protein

del Río, J. A., Gavín, R., (2016). Functions of the cellular prion protein, the end of Moore's law, and Ockham's razor theory Prion 10, (1), 25-40

Since its discovery the cellular prion protein (encoded by the Prnp gene) has been associated with a large number of functions. The proposed functions rank from basic cellular processes such as cell cycle and survival to neural functions such as behavior and neuroprotection, following a pattern similar to that of Moore's law for electronics. In addition, particular interest is increasing in the participation of Prnp in neurodegeneration. However, in recent years a redefinition of these functions has begun, since examples of previously attributed functions were increasingly re-associated with other proteins. Most of these functions are linked to so-called “Prnp-flanking genes” that are close to the genomic locus of Prnp and which are present in the genome of some Prnp mouse models. In addition, their role in neuroprotection against convulsive insults has been confirmed in recent studies. Lastly, in recent years a large number of models indicating the participation of different domains of the protein in apoptosis have been uncovered. However, after more than 10 years of molecular dissection our view is that the simplest mechanistic model in PrPC-mediated cell death should be considered, as Ockham's razor theory suggested.

Keywords: Neurodegeneration, Prion, PrP

Reginensi, Diego, Carulla, Patricia, Nocentini, Sara, Seira, Oscar, Serra-Picamal, Xavier, Torres-Espín, Abel, Matamoros-Angles, Andreu, Gavín, Rosalina, Moreno-Flores, María Teresa, Wandosell, Francisco, Samitier, Josep, Trepat, Xavier, Navarro, Xavier, del Río, José Antonio, (2015). Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord Cellular and Molecular Life Sciences 72, (14), 2719-2737

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.

Keywords: Olfactory ensheathing cells, Traction force microscopy, Chondroitin sulphate proteoglycans, Cell migration, Nogo receptor ectodomain

Vergara, C., Ordóñez-Gutiérrez, L., Wandosell, F., Ferrer, Isidro, 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

Carulla, Patricia, Llorens, Franc, Matamoros-Angles, Andreu, Aguilar-Calvo, Patricia, Espinosa, Juan Carlos, Gavín, Rosalina, Ferrer, Isidre, Legname, Giuseppe, Torres, Juan Maria, del Río, José A., (2015). Involvement of PrPC in kainate-induced excitotoxicity in several mouse strains Scientific Reports 5, 11971

The cellular prion protein (PrPC) has been associated with a plethora of cellular functions ranging from cell cycle to neuroprotection. Mice lacking PrPC show an increased susceptibility to epileptic seizures; the protein, then, is neuroprotective. However, lack of experimental reproducibility has led to considering the possibility that other factors besides PrPC deletion, such as the genetic background of mice or the presence of so-called “Prnp flanking genes”, might contribute to the reported susceptibility. Here, we performed a comparative analysis of seizure-susceptibility using characterized Prnp+/+ and Prnp0/0 mice of B6129, B6.129, 129/Ola or FVB/N genetic backgrounds. Our study indicates that PrPC plays a role in neuroprotection in KA-treated cells and mice. For this function, PrPC should contain the aa32–93 region and needs to be linked to the membrane. In addition, some unidentified “Prnp-flanking genes” play a role parallel to PrPC in the KA-mediated responses in B6129 and B6.129 Prnp0/0 mice.

Ordoñez-Gutiérrez, L., Torres, J. M., Gavín, R., Antón, M., Arroba-Espinosa, A. I., Espinosa, J. C., Vergara, C., del Río, J. A., Wandosell, F., (2013). Cellular prion protein modulates β-amyloid deposition in aged APP/PS1 transgenic mice Neurobiology of Aging 34, (12), 2793-2804

Alzheimer's disease and prion diseases are neuropathological disorders that are caused by abnormal processing and aggregation of amyloid and prion proteins. Interactions between amyloid precursor protein (APP) and PrPc proteins have been described at the neuron level. Accordingly to this putative interaction, we investigated whether β-amyloid accumulation may affect prion infectivity and, conversely, whether different amounts of PrP may affect β-amyloid accumulation. For this purpose, we used the APPswe/PS1dE9 mouse line, a common model of Alzheimer's disease, crossed with mice that either overexpress (Tga20) or that lack prion protein (knock-out) to generate mice that express varying amounts of prion protein and deposit β-amyloid. On these mouse lines, we investigated the influence of each protein on the evolution of both diseases. Our results indicated that although the presence of APP/PS1 and β-amyloid accumulation had no effect on prion infectivity, the accumulation of β-amyloid deposits was dependent on PrPc, whereby increasing levels of prion protein were accompanied by a significant increase in β-amyloid aggregation associated with aging.

Keywords: Aging, Amyloid, Neurodegeneration, Prion, Signaling

Vilches, S., Vergara, C., Nicolás, O., Sanclimens, G., Merino, S., Varón, S., Acosta, G. A., Albericio, F., Royo, M., Del Río, J. A., Gavín, R., (2013). Neurotoxicity of prion peptides mimicking the central domain of the cellular prion protein PLoS ONE 8, (8), e70881

The physiological functions of PrPC remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrPC are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death.

Bribián, Ana, Fontana, Xavier, Llorens, Franc, Gavín, Rosalina, Reina, Manuel, García-Verdugo, José Manuel, Torres, Juan María, de Castro, Fernando, Del Río, J.A., (2012). Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS PLoS ONE 7, (4), e33872

There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrPc) to this process remains unclear. PrPc is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrPc influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrPc proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrPc knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells.

Gavín, R., Ferrer, Isidro, del Río, J. A., (2010). Involvement of Dab1 in APP processing and [beta]-amyloid deposition in sporadic Creutzfeldt-Jakob patients Neurobiology of Disease 37, (2), 324-329

Alzheimer's disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group with PrPsc type 1 showed increased Dab1 phosphorylation and lower [beta]CTF production with an absence of A[beta] deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and [beta]CTF production, and A[beta] deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, A[beta] deposition and PrPsc type in sCJD.

Keywords: Prionopathies, Amyloid plaques, Alzheimer's disease, Dab1