Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice.
Approximately 10% of patients with amyotrophic lateral sclerosis (ALS) have familial ALS (FALS), and 20% of FALS are caused by mutations of superoxide dismutase type 1 (MTSOD1). The fact that some MTSOD1s that cause FALS have full dismutase activity (e.g. G37R) and others no dismutase activity (e.g. G85R) suggests that MTSOD1 causes FALS due to toxicity of the protein rather than a loss in enzymatic function. Compelling data have demonstrated that motor neuron (MN) degeneration can result from a non-cell autonomous effect of the MTSOD1. In order to clarify the role of astrocytes in FALS, we deleted MTSOD1 in astrocytes of G85R transgenic mice. In contrast to a similar study using G37R mice in which astrocyte MTSOD1 loss affected only the late phase of ALS disease, we found that astrocyte MTSOD1 loss in G85R mice delayed disease onset and prolonged the early phase of disease progression, without affecting the late phase. In addition, astrocyte G85R knockdown resulted in decreased microgliosis, decreased SOD1-immunoreactive inclusions and preservation of GLT-1 transporter expression. The differential effects of astrocyte G85R versus G37R knockdown on MN death demonstrate SOD1 mutation-specific effects on ALS pathogenesis; these differences may be a result of the different dismutase activities of the two mutants. The effect of the knockdown of G85R expression in astrocytes on onset as well as disease duration highlights the importance of this cell type in FALS.
Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.
Lijun
L
Wang
David H
DH
Gutmann
Raymond P
RP
Roos
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
D027342:Excitatory Amino Acid Transporter 2; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1