Article abstract
Nature Neuroscience 10, 615 - 622 (2007)
Published online: 15 April 2007 | doi:10.1038/nn1876
Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons
Makiko Nagai1,6,7, Diane B Re1,6,7, Tetsuya Nagata1,6,7, Alcmène Chalazonitis2, Thomas M Jessell3,4,5,6, Hynek Wichterle2,6 & Serge Przedborski1,2,5,6
Abstract
Mutations in superoxide dismutase-1 (SOD1) cause a form of the fatal paralytic disorder amyotrophic lateral sclerosis (ALS), presumably by a combination of cell-autonomous and non–cell-autonomous processes. Here, we show that expression of mutated human SOD1 in primary mouse spinal motor neurons does not provoke motor neuron degeneration. Conversely, rodent astrocytes expressing mutated SOD1 kill spinal primary and embryonic mouse stem cell–derived motor neurons. This is triggered by soluble toxic factor(s) through a Bax-dependent mechanism. However, mutant astrocytes do not cause the death of spinal GABAergic or dorsal root ganglion neurons or of embryonic stem cell–derived interneurons. In contrast to astrocytes, fibroblasts, microglia, cortical neurons and myocytes expressing mutated SOD1 do not cause overt neurotoxicity. These findings indicate that astrocytes may play a role in the specific degeneration of spinal motor neurons in ALS. Identification of the astrocyte-derived soluble factor(s) may have far-reaching implications for ALS from both a pathogenic and therapeutic standpoint.
- Department of Neurology, Columbia University, 710 West 168th Street, New York, New York 10032, USA.
- Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
- Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
- Howard Hughes Medical Institute, Columbia University, 701 West 168th Street, New York, New York 10032, USA.
- Center for Neurobiology and Behavior, 1051 Riverside Drive, Columbia University, New York, New York 10032, USA.
- Center for Motor Neuron Biology and Disease, Columbia University, 701 West 168th Street, New York, New York 10032, USA.
- These authors contributed equally to this work.
Correspondence to: Serge Przedborski1,2,5,6 e-mail: SP30@Columbia.edu
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