title: Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo.
abstract: Recent studies highlight astrocytes as key drivers of motor neuron (MN) degeneration and disease propagation in mutant human superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis. However, in vivo analysis of specific astrocytic influence in amyotrophic lateral sclerosis has proven difficult because mSOD1 is ubiquitously expressed throughout the CNS of rodent models studied. Here, we transplanted SOD1(G93A) glial-restricted precursor cells--glial progenitors capable of differentiating into astrocytes--into the cervical spinal cord of WT rats to reveal how mutant astrocytes influence WT MNs and other cells types (microglia and astrocytes) in an in vivo setting. Transplanted SOD1(G93A) glial-restricted precursor cells survived and differentiated efficiently into astrocytes. Graft-derived SOD1(G93A) astrocytes induced host MN ubiquitination and death, forelimb motor and respiratory dysfunction, reactive astrocytosis, and reduced GLT-1 transporter expression in WT animals. The SOD1(G93A) astrocyte-induced MN death seemed in part mediated by host microglial activation. These findings show that mSOD1 astrocytes alone can induce WT MN death and associated pathological changes in vivo.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sophia T
authors.initials: ST
authors.lastname: Papadeas
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kraig
authors.forename: Colin
authors.initials: C
authors.lastname: O'Banion
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Lepore
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics*; D009457:Neuroglia / Q000637:transplantation; D017354:Point Mutation / Q000235:genetics*; D051381:Rats; D033581:Stem Cell Transplantation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D054875:Ubiquitination
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1