title: The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis.
abstract: Mutant superoxide dismutase type 1 (MTSOD1), the most common known cause of familial amyotrophic lateral sclerosis (FALS), is believed to cause FALS as a result of a toxicity of the protein. MTSOD1s with full dismutase enzymatic activity (e.g., G37R) and without any enzymatic activity (e.g., G85R) cause FALS, demonstrating that the ability of MTSOD1 to cause FALS is not dependent on the dismutase activity; however, it remains unclear whether MTSOD1 dismutase activity can influence disease phenotype. In the present study, we selectively knocked down G85R expression in particular cell types of G85R mice. Results following knockdown of G85R in motor neurons (MNs)/interneurons of G85R mice were similar to results from a published study involving knockdown of G37R in G37R mice; however, G85R knockdown in microglia/macrophages induced a prolonged early and late disease phase while G37R knockdown in the same cells only affected late phase. These results show that: (i) MN as well as non-MN expression of G85R, like G37R, has a significant effect on disease in transgenic mice - indicating the role of non-cell autonomous degeneration in both dismutase-active and inactive MTSOD1s. (ii) The effect of MTSOD1 expression in microglia/macrophages varies with different mutants, and may be influenced by the MTSOD1's dismutase activity.
authors.affiliation: Department of Neurology/MC2030, The University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Kamal
authors.initials: K
authors.lastname: Sharma
authors.forename: Gabriella
authors.initials: G
authors.lastname: Grisotti
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D018450:Disease Progression; D005190:Family; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1