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

Gerstmann-Straussler-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.The authors thank Tom Yohannan for editorial advice and M. Segura-Feliu for technical assistance. We thank members of the Del Rio, Sanchez-Pernaute, Castilla, Raya, Consiglio, Lopez de Munain and Ferrer groups for stimulating discussions and ideas. We also thank to Lidia Bardia of the Advanced Confocal Microscopy service of the IRB-PCB for helping us with mitochondria tracking experiments. This research was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) (BFU2015-67777-R), the Spanish prion network (Prionet Spain, AGL2015-71764-REDT), the Generalitat de Catalunya (SGR2014-1218), CIBERNED (PI2014/02-4 (Rapid dementias) and PI2016/02 (MFDEND)), La Caixa Obra Social Foundation, La Marato de TV3 to J.A.D.R.. R.S.P was funded by the Joint Program in Neurodegenerative Diseases (DAMNDPATHS, AC14/00021). J.C. was funded by MINECO (AGL2015-65046-C2-1-R) and EiTB Maratoia (BioEF): BIO12/AL/004. A.R. was supported by MINECO (SAF2015-69706-R), Instituto de Salud Carlos III/FEDER (TerCel RD16/0011/0024, PIE14/00061), AGAUR (2014-SGR-1460), and Fundacio La Marato de TV3 (201534-30) and CERCA Programme/Generalitat de Catalunya. I.F. was funded was supported by grants from CIBERNED (PI2014/02-4 Rapid dementias) and Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III), and co-funded by FEDER funds/European Regional Development Fund (ERDF) - a way to build Europe PIE14/00034 and PI14/00757. A.C. was also supported by BFU2013-49157-P and RETICTerCel grants from MINECO and the European Research Council (ERC) 2012-StG (311736- PD-HUMMODEL). A.L.M. was funded by grants from Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III (PI14/00436)), and the Joint Program in Neurodegenerative Diseases (DEMTEST). A.M-A. was supported by a fellowship from the Fundacion Tatiana Perez de Guzman el Bueno. L.M.G. was supported by a CONACYT fellowship (CVU 357631, Mexico). The authors declare no conflicts of interest