Staff member


Ignasi Ferrer Lluis

PhD Student
Biomedical Signal Processing and Interpretation
iferrer@ibecbarcelona.eu

Staff member publications

Urrea, L., Segura-Feliu, M., Masuda-Suzukake, M., Hervera, A., Pedraz, L., Aznar, J. M. G., Vila, M., Samitier, J., Torrents, E., Ferrer, I., Gavín, R., Hagesawa, M., Del Río, J. A., (2017). Involvement of cellular prion protein in Molecular Neurobiology online, 1-14

The cellular prion protein, encoded by the gene Prnp, has been reported to be a receptor of

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, 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


Ferrer, I., Llorens, F., Frau-Mendez, L., Fernandez-Vega, I., Thune, K., del Río, J. A., Schmizt, M., Ansoleaga, B., Gotzmann, N., Cramm, M., Zerr, I., Zarranz, Juan José, (2016). EfiIdentification of new molecular alterations in Fatal Familial Insomnia Prion PRION 2016 , Taylor & Francis (Tokyo, Japan) 10, (Supplement), P-092

Fatal familial insomnia (FFI) is an autosomal dominant prion disease caused by a D178N mutation in PRNP in combination with methionine at codon 129 in the mutated allele of the same gene. The present study analyzes pathological and molecular features in 7 FFI cases carrying the mutation D178N and M homozygous at the codon 129 of PRNP. Severe neuronal loss and marked astrocytic gliosis was observed in every case in the mediodorsal and anterior nuclei of the thalamus whereas the entorhinal cortex (EC) was variably affected. Spongiform degeneration was only observed in the EC. Synaptic and fine granular PrPSc immunoreactivity was found in the EC but not in thalamus. Microglia was barely increased in the mediodorsal thalamus, but mRNA expression of IL6, IL10RA, CSF3R and TLR7 was found in the thalamus in FFI. PrPC levels were significantly decreased in the thalamus, EC and cerebellum in FFI compared with controls. However, increased expression of the non-glycosylated band of about 19 kDa was observed in the thalamus when using PrP antibodies mapping to the central region of the PrP comprising the


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, F., Ferrer, I., del Río, J. A., (2014). Gene expression resulting from PrPC ablation and PrPC overexpression in murine and cellular models Molecular Neurobiology 49, (1), 413-423

The cellular prion protein (PrPC) plays a key role in prion diseases when it converts to the pathogenic form scrapie prion protein. Increasing knowledge of its participation in prion infection contrasts with the elusive and controversial data regarding its physiological role probably related to its pleiotropy, cell-specific functions, and cellular-specific milieu. Multiple approaches have been made to the increasing understanding of the molecular mechanisms and cellular functions modulated by PrPC at the transcriptomic and proteomic levels. Gene expression analyses have been made in several mouse and cellular models with regulated expression of PrPC resulting in PrPC ablation or PrPC overexpression. These analyses support previous functional data and have yielded clues about new potential functions. However, experiments on animal models have shown moderate and varied results which are difficult to interpret. Moreover, studies in cell cultures correlate little with in vivo counterparts. Yet, both animal and cell models have provided some insights on how to proceed in the future by using more refined methods and selected functional experiments.


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., Ansoleaga, B., Garcia-Esparcia, P., Zafar, S., Grau-Rivera, O., López-González, I., Blanco, R., Carmona, M., Yagüe, J., Nos, C., Del Río, J. A., Gelpí, E., Zerr, I., Ferrer, I., (2013). PrP mRNa and protein expression in brain and PrPc in CSF in Creutzfeldt-Jakob disease MM1 and VV2 Prion 7, (5), 383-393

Creutzfeldt-Jakob disease (cJD) is a heterogenic neurodegenerative disorder associated with abnormal posttranslational processing of cellular prion protein (PrPc). cJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrPsc (type 1:20/21 kDa and type 2:19 kDa). MM1 and VV2 are the most common sporadic cJD (scJD) subtypes. PrP mRNa expression levels in the frontal cortex and cerebellum are reduced in scJD in a form subtype-dependent. Total PrP protein levels and PrPsc levels in the frontal cortex and cerebellum accumulate differentially in scJD MM1 and scJD VV2 with no relation between PrPsc deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the cSF, reduced PrPc, the only form present in this compartment, occurs in scJD MM1 and VV2. PrP mRNa expression is also reduced in the frontal cortex in advanced stages of alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrPc levels in brain varies from one disease to another. Reduced PrPc levels in cSF correlate with PrP mRNa expression in brain, which in turn reflects severity of degeneration in scJD.


Martí, E., Pantano, L., Bañez-Coronel, M., Llorens, F., Miñones-Moyano, E., Porta, S., Sumoy, L., Ferrer, I., Estivill, X., (2010). A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing Nucleic Acids Research 38, (20), 7219-7235

Huntington disease (HD) is a neurodegenerative disorder that predominantly affects neurons of the forebrain. We have applied the Illumina massively parallel sequencing to deeply analyze the small RNA populations of two different forebrain areas, the frontal cortex (FC) and the striatum (ST) of healthy individuals and individuals with HD. More than 80% of the small-RNAs were annotated as microRNAs (miRNAs) in all samples. Deep sequencing revealed length and sequence heterogeneity (IsomiRs) for the vast majority of miRNAs. Around 80–90% of the miRNAs presented modifications in the 3′-terminus mainly in the form of trimming and/or as nucleotide addition variants, while the 5′-terminus of the miRNAs was specially protected from changes. Expression profiling showed strong miRNA and isomiR expression deregulation in HD, most being common to both FC and ST. The analysis of the upstream regulatory regions in co-regulated miRNAs suggests a role for RE1-Silencing Transcription Factor (REST) and P53 in miRNAs downregulation in HD. The putative targets of deregulated miRNAs and seed-region IsomiRs strongly suggest that their altered expression contributes to the aberrant gene expression in HD. Our results show that miRNA variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions.

Keywords: -----


Gavín, R., Ferrer, I., 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


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