iPS Cell Cultures from a Gerstmann-Sträussler-Scheinker Patient with the Y218N PRNP Mutation Recapitulate tau Pathology

Mol Neurobiol DOI 10.1007/s12035-017-0506-6 iPS Cell Cultures from a Gerstmann-Sträussler-Scheinker Patient with the Y218N PRNP Mutation Recapitulate tau Pathology Andreu Matamoros-Angles 1,2,3,4 & Lucía Mayela Gayosso 5,6,7 & Yvonne Richaud-Patin 8,9 & Angelique di Domenico 10,11 & Cristina Vergara 1,2,3,4,12 & Arnau Hervera 1,2,3,4 & Amaya Sousa 5 & Natalia Fernández-Borges 6,7,13 & Antonella Consiglio 10,11,14 & Rosalina Gavín 1,2,3,4 & Rakel López de Maturana 5 & Isidro Ferrer 3,4,11 & Adolfo López de Munain 15,16,17 & Ángel Raya 8,9,18 & Joaquín Castilla 6,7 & Rosario Sánchez-Pernaute 5,19 & José Antonio del Río 1,2,3,4 Received: 7 December 2016 / Accepted: 21 March 2017 # The Author(s) 2017. This article is an open access publication Abstract 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 Andreu Matamoros-Angles, Lucía Mayela Gayosso, and Yvonne Richaud-Patin contribute equally to this study. Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0506-6) contains supplementary material, which is available to authorized users. * Ángel Raya 8 Centre de Medicina Regenerativa de Barcelona, c/ Dr. Aiguader 88, 08003 Barcelona, Spain * Joaquín Castilla 9 Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid, Spain * Rosario Sánchez-Pernaute 10 Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain * José Antonio del Río ; 11 Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain 12 Present address: Laboratory of Histology, Neuroanatomy and Neuropathology (CP 620), ULB Neuroscience Institute. Université Libre de Bruxelles, Faculty of Medicine, Brussels, Belgium 1 Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028 Barcelona, Spain 2 Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain 13 Present address: CISA-INIA, Center for Animal Health Research, Madrid, Spain 3 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain 14 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy 4 Institute of Neuroscience, University of Barcelona, Barcelona, Spain 15 5 Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain Instituto Biodonostia-Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain 16 6 Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain Neurosciences Department, University of the Basque Country UPV-EHU, Bilbao, Spain 7 IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain 17 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), San Sebastian, Gipuzkoa, Spain Mol Neurobiol 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 Gerstmann-Sträussler-Scheinker . Induced pluripotent stem cells . Tau . Cellular prion protein Introduction Biomedical research on neurodegenerative diseases with low prevalence in humans relies on the possibility of analyzing brain samples only at very late stages of the disease. Thus, our view of the biochemical or molecular changes during the disease is partial. This drawback steadily increases with a faster neurodegenerative progression speed (e.g., in prionopathies [1] or rapid Alzheimer’s disease [2]). This is also the case for most sporadic taupathies and in most cases of frontotemporal lobar degeneration (FTLD) displaying neurofibrillary degeneration [3, 4]. This limitation impedes the study of early onset changes in asymptomatic patients, making it impossible to investigate illness evolution, therefore hampering biochemical/molecular studies and drug discovery [5]. Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare autosomal dominant neurodegenerative prionopathy clinically characterized by a wide spectrum of manifestations including but not limited to ataxia, spastic paraparesis, extrapyramidal signs and dementia [6, 5]. Most GSS patients have the P102L mutation in the cellular prion protein (PrPC) gene (PRNP) located in the short arm of chromosome 20 [5]. Cases of rapid progressive forms of GSS are rare [7] with an average duration after clinical diagnosis of 5–6 years (from 6 months to 13 years) [8, 5]. Histopathological examination of postmortem GSS brains has revealed abnormal misfolded prion (PrP) aggregates in the form of unicentric and multicentric deposits in the cerebellum and cortical gray matter [5]. In addition, western blot analysis of aggregated PrP is distinguished by the presence of truncated protein fragments ranging between 6 and 10 KDa and a variable number of bands of higher molecular weight [9]. Parallel to this particular PrP 18 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 19 Present address: Andalusian Initiative for Advanced Therapies, Junta de Andalusia, Seville, Spain deposition, pathological features characteristic of other neurodegenerative diseases such us parkinsonism or Alzheimer’s disease have been observed in some GSS patients [5]. Indeed, an increase in hyperphosphorylated Tau is frequently observed in the pathological analysis of brains from GSS patients carrying PRNP mutations P102L [10], P105L [11], A117V [12], V176G [13], F198S [14, 15], Q217R [16, 15] and Y218N [17]. Although it has been shown that PrPC with the P102L mutation display an increased binding to Tau [18], the role of these point mutations in the development of neurofibrillary degeneration is unknown. Nevertheless, in some P102L GSS cases with increased levels of p-Tau, the distribution of p-Tau tangles close to PrP deposits suggesting an active participation of PrP in the generation of p-Tau [10]. Due to the above-mentioned restrictions in this study we explored the usefulness of an induced (...truncated)