1. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells.
- Author
-
Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, and Gage FH
- 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
- 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.
- Published
- 2008
- Full Text
- View/download PDF