title: Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks.
abstract: Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration.
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Canals
authors.affiliation: Departament d'Estructura i Constituents de la Matèria, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Soriano
authors.affiliation: Departament d'Estructura i Constituents de la Matèria, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Javier G
authors.initials: JG
authors.lastname: Orlandi
authors.affiliation: Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Torrent
authors.affiliation: Centre de Medicina Regenerativa de Barcelona and Control of Stem Cell Potency Group, Institut de Bioenginyeria de Catalunya, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomaterials y Nanomedicina, 28029 Madrid, Spain.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Richaud-Patin
authors.affiliation: Centre de Medicina Regenerativa de Barcelona and Control of Stem Cell Potency Group, Institut de Bioenginyeria de Catalunya, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomaterials y Nanomedicina, 28029 Madrid, Spain.
authors.forename: Senda
authors.initials: S
authors.lastname: Jiménez-Delgado
authors.affiliation: Health Sciences Department, Universita' del Piemonte Orientale, 28100 Novara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Merlin
authors.affiliation: Health Sciences Department, Universita' del Piemonte Orientale, 28100 Novara, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.affiliation: Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain; Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Consiglio
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain; Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain. Electronic address: dgrinberg@ub.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.affiliation: Centre de Medicina Regenerativa de Barcelona and Control of Stem Cell Potency Group, Institut de Bioenginyeria de Catalunya, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomaterials y Nanomedicina, 28029 Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain. Electronic address: araya@cmrb.eu.
authors.forename: Angel
authors.initials: A
authors.lastname: Raya
mesh_terms: D018929:Cell Culture Techniques; D002478:Cells, Cultured; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D009084:Mucopolysaccharidosis III / Q000473:pathology*; D009415:Nerve Net / Q000473:pathology*; D055495:Neurogenesis; D009474:Neurons / Q000473:pathology*