Rosalina Gavín Marín | University of Barcelona (original) (raw)

Papers by Rosalina Gavín Marín

Progress in neurobiology, Jan 9, 2018

Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-sy... more 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 (PrP) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrP interaction takes place in two differently charged clusters of PrP. In addition to β-amyloid, participation of PrP in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrP as a putative receptor for amy...

Scientific Reports, 2015

The cellular prion protein (PrPC) has been associated with a plethora of cellular functions rangi... more 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 an...

Cells, 2020

Cellular (also termed ‘natural’) prion protein has been extensively studied for many years for it... more 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...

Molecular neurobiology, Jan 22, 2017

The cellular prion protein, encoded by the gene Prnp, has been reported to be a receptor of β-amy... more 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 PrP(C)-overexpressing mice. In addition, α-synuclein binds strongly on PrP(C)-expressing cells, suggesting a role in modulating the effect of α-synuclein fibrils.

Molecular neurobiology, Jan 10, 2016

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adul... more 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 d...

Molecular Biology of the Cell, 2011

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When muta... more Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC 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 Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore...

Brain Research Reviews, 2009

International Journal of Molecular Sciences, 2021

Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it ... more Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. O...

Las "Aeromonas" spp. estan implicadas en diversos procesos infecciosos, que afectan des... more Las "Aeromonas" spp. estan implicadas en diversos procesos infecciosos, que afectan desde animales poiquilotermos a humanos. El genero cuenta con distintos determinantes patogenicos que interactuan a diferente nivel para producir la enfermedad, siendo uno de estos el flagelo. En este trabajo describimos cinco genes de "A. caviae" Sch3N, implicados en el proceso de adhesion a celulas eucariotas HEp-2 a traves del ensamblaje del flagelo, asi como de la biosintesis del antigeno O del lipopolisacarido, y estudiamos su distribucion en el genero. Paralelamente constatamos la existencia de dos sistemas independientes de flagelacion en las aeromonas, polar y lateral respectivamente. Asi mismo caracterizamos genetica y fenotipicamente los loci de las flagelinas laterales de "A. hydrophila" AH-3 (una flagelina) y "A. caviae" Sch3N (dos flagelinas), asi como los genes acompanantes que constituyen el locus "laf" de la primera cepa mencionada. Es...

PLoS ONE, 2013

The physiological functions of PrP C remain enigmatic, but the central domain, comprising highly ... more The physiological functions of PrP C 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 PrP C 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.

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of... more 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 (PrP C ) 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 PrP C expression in the development of AD, and a putative relationship between PrP C and tau processing is emerging. However, the role of tau/PrP C interaction in AD is poorly understood. In this study, we show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrP C knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrP C 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 PrP C 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.