Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

Authors
Oliveira, L. M. A.; Falomir Lockhart, Lisandro Jorge; Botelho, M. G.; Lin, K. H.; Wales, P.; Koch, J. C.; Gerhardt, Elizabeth; Taschenberger, H.; Outeiro, T. F.; Lingor, P.; Schüele, B.; Arndt Jovin, D. J.; Jovin, T. M.
Publication Year
2015
Language
English
Format
article
Status
Published version
Description
We have assessed the impact of α-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson´s disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of α-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson´s disease progression, particularly in the context of bioenergetic dysfunction.
Fil: Oliveira, L. M. A.. Max-Planck-Institut für biophysikalische Chemie; Alemania
Fil: Falomir Lockhart, Lisandro Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina. Max-Planck-Institut für biophysikalische Chemie; Alemania
Fil: Botelho, M. G.. Max-Planck-Institut für biophysikalische Chemie; Alemania. Universidade Federal do Rio de Janeiro; Brasil
Fil: Lin, K. H.. Max-Planck-Institut für biophysikalische Chemie; Alemania
Fil: Wales, P.. Universität Göttingen; Alemania
Fil: Koch, J. C.. Universität Göttingen; Alemania
Fil: Gerhardt, Elizabeth. Universität Göttingen; Alemania
Fil: Taschenberger, H.. Max-Planck-Institut für biophysikalische Chemie; Alemania
Fil: Outeiro, T. F.. Universität Göttingen; Alemania
Fil: Lingor, P.. Universität Göttingen; Alemania
Fil: Schüele, B.. The Parkinson’s Institute; Estados Unidos
Fil: Arndt Jovin, D. J.. Max-Planck-Institut für biophysikalische Chemie; Alemania
Fil: Jovin, T. M.. Max-Planck-Institut für biophysikalische Chemie; Alemania
Subject
Parkinson´s disease
Alpha-Synuclein
Gene triplication
Induced-Pluripotent Stem-like Cells
Otras Ciencias Biológicas
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Open access
License
https://creativecommons.org/licenses/by/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/49067