title: Chronic infusion of SOD1G93Aastrocyte-secreted factors induces spinal motoneuron degeneration and neuromuscular dysfunction in healthy rats.
abstract: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease and studies in vitro show that motoneuron degeneration is triggered by non-cell-autonomous mechanisms. However, whether soluble toxic factor(s) released by mutant superoxide dismutase 1 (SOD1) expressing astrocytes induces death of motoneurons and leads to motor dysfunction in vivo is not known. To directly test this, healthy adult rats were treated with conditioned media derived from primary mouse astrocytes (ACM) that express human (h) SOD1G93A(ACM-hG93A) via chronic osmotic pump infusion in the lumbar spinal cord. Controls included ACM derived from transgenic mice expressing hSOD1WT(ACM-hWT) or non-transgenic mouse SOD1WT(ACM-WT) astrocytes. Rats chronically infused with ACM-hG93A started to develop motor dysfunction at 8 days, as measured by rotarod performance. Additionally, immunohistochemical analyses at day 16 revealed reactive astrogliosis and significant loss of motoneurons in the ventral horn of the infused region. Controls did not show significant motor behavior alterations or neuronal damage. Thus, we demonstrate that factors released in vitro from astrocytes derived from ALS mice cause spinal motoneuron death and consequent neuromuscular dysfunction in vivo.
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, México.
authors.forename: Uri N
authors.initials: UN
authors.lastname: Ramírez-Jarquín
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Rojas
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, México.
authors.forename: Ricardo
authors.identifier: http://orcid.org/0000-0001-8948-0140
authors.initials: R
authors.lastname: Tapia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001522:Behavior, Animal; D016923:Cell Death; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism*; D004195:Disease Models, Animal; D005911:Gliosis; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D061251:Primary Cell Culture; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D013127:Spinal Nerves / Q000378:metabolism* / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: ALS; excitotoxicity; motoneuron; soluble toxic factors