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Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells.
- Source :
-
Cell stem cell [Cell Stem Cell] 2008 Dec 04; Vol. 3 (6), pp. 649-57. - Publication Year :
- 2008
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. ALS can be induced by mutations in the superoxide dismutase 1 gene (SOD1). Evidence for the non-cell-autonomous nature of ALS emerged from the observation that wild-type glial cells extended the survival of SOD1 mutant motor neurons in chimeric mice. To uncover the contribution of astrocytes to human motor neuron degeneration, we cocultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1. We detected a selective motor neuron toxicity that was correlated with increased inflammatory response in SOD1-mutated astrocytes. Furthermore, we present evidence that astrocytes can activate NOX2 to produce superoxide and that effect can be reversed by antioxidants. We show that NOX2 inhibitor, apocynin, can prevent the loss of motor neurons caused by SOD1-mutated astrocytes. These results provide an assay for drug screening using a human ALS in vitro astrocyte-based cell model.
- Subjects :
- Acetophenones pharmacology
Acetophenones therapeutic use
Animals
Astrocytes cytology
Biological Assay methods
Cell Communication genetics
Cell Differentiation genetics
Cell Line
Cell Lineage genetics
Cell Survival genetics
Cells, Cultured
Drug Evaluation, Preclinical methods
Embryonic Stem Cells cytology
Enzyme Inhibitors pharmacology
Humans
Membrane Glycoproteins metabolism
Motor Neurons metabolism
Mutation genetics
NADPH Oxidase 2
NADPH Oxidases metabolism
Nerve Degeneration genetics
Nerve Degeneration physiopathology
Oxidative Stress drug effects
Oxidative Stress physiology
Rats
Superoxide Dismutase-1
Superoxides metabolism
Superoxides toxicity
Amyotrophic Lateral Sclerosis genetics
Astrocytes metabolism
Embryonic Stem Cells metabolism
Motor Neurons cytology
Nerve Degeneration enzymology
Superoxide Dismutase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1875-9777
- Volume :
- 3
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell stem cell
- Publication Type :
- Academic Journal
- Accession number :
- 19041781
- Full Text :
- https://doi.org/10.1016/j.stem.2008.10.001