Back to Search
Start Over
Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells
- Source :
- Stem Cell Reports, Stem Cell Reports, Vol 6, Iss 4, Pp 496-510 (2016)
- Publisher :
- The Authors. Published by Elsevier Inc.
-
Abstract
- Summary Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.<br />Graphical Abstract<br />Highlights • Modeling familial ALS (FALS) using iPSC-derived motor neurons • Aberrant gene expression and/or splicing in FALS motor neuron precursor cells • Mis-localization of mutant FUS protein in FALS motor neurons • Increased apoptosis of FALS motor neurons<br />Okano, Yano, and colleagues established iPSCs from two familial ALS patients with the missense mutation in the FUS gene and differentiated them into motor neurons as a novel in vitro model for ALS. Moreover, this model enables the pursuit of correlations and new discovery of molecular pathophysiology in various cell biological phenomena by endogenous mutation in patient-derived motor neurons.
- Subjects :
- 0301 basic medicine
Male
medicine.disease_cause
Biochemistry
Cytosol
Missense mutation
Amyotrophic lateral sclerosis
Induced pluripotent stem cell
lcsh:QH301-705.5
Cells, Cultured
Genetics
Gene Editing
Motor Neurons
lcsh:R5-920
Mutation
Reverse Transcriptase Polymerase Chain Reaction
Homozygote
Cell Differentiation
Phenotype
Cell biology
Pedigree
medicine.anatomical_structure
Female
lcsh:Medicine (General)
Adult
Heterozygote
Induced Pluripotent Stem Cells
Mutation, Missense
Biology
Article
03 medical and health sciences
Young Adult
Stress granule
medicine
Humans
Gene
Family Health
Base Sequence
Models, Genetic
Gene Expression Profiling
Amyotrophic Lateral Sclerosis
Cell Biology
Motor neuron
medicine.disease
030104 developmental biology
lcsh:Biology (General)
Microscopy, Fluorescence
RNA-Binding Protein FUS
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 22136711
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Stem Cell Reports
- Accession number :
- edsair.doi.dedup.....35ddb844437f34cd1e8d586679ca95a3
- Full Text :
- https://doi.org/10.1016/j.stemcr.2016.02.011