title: Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1.
abstract: Although the aberrant assembly of mutant superoxide dismutase 1 (mSOD1) is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the molecular basis of superoxide dismutase 1 (SOD1) oligomerization remains undetermined. We investigated the roles of transglutaminase 2 (TG2), an endogenous cross-linker in mSOD1-linked ALS. TG2 interacted preferentially with mSOD1 and promoted its oligomerization in transfected cells. Purified TG2 directly oligomerized recombinant mutant SOD1 and the apo-form of the wild-type SOD1 proteins in a calcium-dependent manner, indicating that misfolded SOD1 is a substrate of TG2. Moreover, the non-cell-autonomous effect of extracellular TG2 on the neuroinflammation was suggested, since the TG2-mediated soluble SOD1 oligomers induced tumor necrosis factor-α, interleukin-1β, and nitric oxide in microglial BV2 cells. TG2 was up-regulated in the spinal cord of pre-symptomatic G93A SOD1 transgenic mice and in the hypoglossal nuclei of mice suffering nerve ligation. Furthermore, inhibition of spinal TG2 by cystamine significantly delayed the progression and reduced SOD1 oligomers and microglial activation. These results indicate a novel role of TG2 in SOD1 oligomer-mediated neuroinflammation, as well as in the involvement in the intracellular aggregation of misfolded SOD1 in ALS.
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan; Department of Neurology, Kyoto University Graduate school of Medicine, Kyoto, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Oono
authors.forename: Ayako
authors.initials: A
authors.lastname: Okado-Matsumoto
authors.forename: Akemi
authors.initials: A
authors.lastname: Shodai
authors.forename: Akemi
authors.initials: A
authors.lastname: Ido
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohta
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D019204:GTP-Binding Proteins / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D007002:Hypoglossal Nerve / Q000473:pathology; D047468:Immunoprecipitation; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D017510:Protein Folding / Q000187:drug effects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000187:drug effects*; D000072105:Superoxide Dismutase-1; D011503:Transglutaminases / Q000633:toxicity*
chemical_list: D018076:DNA, Complementary; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: amyotrophic lateral sclerosis; microglia; non-cell-autonomous; oligomer; superoxide dismutase 1; transglutaminase 2