title: Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.
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.
authors: Department of Neurology, Columbia University, 710 West 168th Street, New York, New York 10032, USA.
authors: Makiko
authors: M
authors: Nagai
authors: Diane B
authors: DB
authors: Re
authors: Tetsuya
authors: T
authors: Nagata
authors: Alcmène
authors: A
authors: Chalazonitis
authors: Thomas M
authors: TM
authors: Jessell
authors: Hynek
authors: H
authors: Wichterle
authors: Serge
authors: S
authors: Przedborski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000737:chemistry* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase