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Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells
- Source :
- CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET, Cell Death and Disease, Cell Death & Disease, SEDICI (UNLP), Universidad Nacional de La Plata, instacron:UNLP
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- We have assessed the impact of a-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 a-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.<br />Instituto de Investigaciones Bioquímicas de La Plata
- Subjects :
- Cancer Research
Alpha-Synuclein
Neurite
Otras Ciencias Biológicas
Cellular differentiation
Induced Pluripotent Stem Cells
Immunology
Nuclear receptor related-1 protein
α-synuclein
Parkinson's
pluripotent stem cells
Biology
Induced-Pluripotent Stem-like Cells
purl.org/becyt/ford/1 [https]
Ciencias Biológicas
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Protein α-synuclein
Humans
Progenitor cell
purl.org/becyt/ford/1.6 [https]
Induced pluripotent stem cell
Cells, Cultured
030304 developmental biology
Neurons
0303 health sciences
Tyrosine hydroxylase
Gene triplication
Gene Expression Profiling
Neurogenesis
Cell Differentiation
Parkinson Disease
Cell Biology
Molecular biology
Parkinson´s disease
Gene expression profiling
Ciencias Médicas
alpha-Synuclein
biology.protein
Original Article
CIENCIAS NATURALES Y EXACTAS
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....18fe8f6c4ef802c66a21b9a7e76672a7