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Chronic infusion of SOD1 G93A astrocyte‐secreted factors induces spinal motoneuron degeneration and neuromuscular dysfunction in healthy rats
Author(s) -
RamírezJarquín Uri N.,
Rojas Fabiola,
van Zundert Brigitte,
Tapia Ricardo
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25827
Subject(s) - sod1 , astrogliosis , astrocyte , amyotrophic lateral sclerosis , spinal cord , in vivo , motor neuron , superoxide dismutase , genetically modified mouse , medicine , biology , endocrinology , pathology , neuroscience , transgene , oxidative stress , central nervous system , biochemistry , disease , microbiology and biotechnology , gene
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) SOD1 G93A (ACM‐hG93A) via chronic osmotic pump infusion in the lumbar spinal cord. Controls included ACM derived from transgenic mice expressing hSOD1 WT (ACM‐hWT) or non‐transgenic mouse SOD1 WT (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.