title: Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease.
abstract: Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.
authors.affiliation: Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sánchez-Danés
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Richaud-Patin
authors.forename: Iria
authors.initials: I
authors.lastname: Carballo-Carbajal
authors.forename: Senda
authors.initials: S
authors.lastname: Jiménez-Delgado
authors.forename: Carles
authors.initials: C
authors.lastname: Caig
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Guglielmo
authors.forename: Mario
authors.initials: M
authors.lastname: Ezquerra
authors.forename: Bindiben
authors.initials: B
authors.lastname: Patel
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.forename: Maurizio
authors.initials: M
authors.lastname: Memo
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: José
authors.initials: J
authors.lastname: López-Barneo
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: Eduard
authors.initials: E
authors.lastname: Tolosa
authors.forename: Antonella
authors.initials: A
authors.lastname: Consiglio
authors.forename: Angel
authors.initials: A
authors.lastname: Raya
mesh_terms: D001343:Autophagy; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology*; D039904:Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology*; D011954:Receptors, Dopamine / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D011954:Receptors, Dopamine; D004298:Dopamine