English

Ayako Okado-Matsumoto, Ph.D. / Associate Professor

Research interests

Molecular mechanism of SOD1-aggregation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by selective loss of motor neurons with unknown etiology. The formation of insoluble aggregates of Cu, Zn-superoxide dismutase (SOD1) is a hallmark in ALS. Data obtained using conformationally restricted antibodies suggest that soluble misfolded SOD1 forms could be present in both sporadic and familial ALS patients. Oligomeric forms of misfolded proteins may underlie several neurodegenerative disorders, including Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease.

The human transglutaminases are a protein family consisting of a protein 4.2, that lacks catalytic activity, and eight enzymes designated blood coagulation factor XIII-a, transglutaminase 1 (TG1), TG2, TG3, TG4, TG5, TG6, and TG7, that catalyze a variety of Ca2+- and thiol-dependent posttranslational protein modifications. TG2 is ubiquitously expressed in both intracellular and extracellular spaces of the central nervous system. TG2 has been reported to oligomerize pathogenic proteins such as α-synuclein, β-amyloid, and huntingtin. In addition, targeting TG2 has therapeutic effects in animal models of Huntington’s disease and TG2 is elevated in the brain and cerebrospinal fluid of patients with ALS and Huntington’s disease.

The role of catalytic activity of TG2 in ALS pathogenesis is unknown. We found that TG2 recognized and oligomerized mSOD1, but not native WT SOD1 in vitro and in cultured cells. We investigated the role of TG2 in mSOD1 oligomer formation, and found that TG2 is involved in the aberrant assembly of misfolded SOD1 proteins, which contribute to neuroinflammation and disease progression in a mouse model of ALS.

Present research themes

Modification of Cys111 to inhibit oligomer formation of SOD1 in amyotrophic lateral sclerosis.
Posttranslational modification of erythrocyte α-synuclein as a potential biomarker for neurodegenerative disease.
Mitochondrial dysfunction and formation of supercomplexes of respiratory chain in leukocytes as a potential biomarker for neurodegenerative disease.

Publication

Hara T, Amagai R, Koga M, Okado-Matsumoto A: Mitochondrial respiratory chain supercomplexes in human mononuclear leukocytes. Int J Anal Bio-Sci 4, 6-12 2016
Oono M*, Okado-Matsumoto A*, Shodai A, Ido A, Ohta Y, Abe K, Ayaki T, Ito H, Takahashi R, Taniguchi N, Urushitani M. Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1. J Neurochem. 2013 Aug 30. [Epub ahead of print] (*contributed equally)
Okado-Matsumoto A, Fridovich I. Putative denitrosylase activity of Cu,Zn-superoxide dismutase. Free Radic Biol Med. 2007 Sep 1;43(5):830-6.
Okado-Matsumoto A, Guan Z, Fridovich I. Modification of cysteine 111 in human Cu,Zn-superoxide dismutase. Free Radic Biol Med. 2006 Dec 15;41(12):1837-46.
Batinić-Haberle I, Spasojević I, Stevens RD, Bondurant B, Okado-Matsumoto A, Fridovich I, Vujasković Z, Dewhirst MW. New PEG-ylated Mn(III) porphyrins approaching catalytic activity of SOD enzyme. Dalton Trans. 2006 Jan 28;(4):617-24.
Batinić-Haberle I, Spasojević I, Stevens RD, Hambright P, Neta P, Okado-Matsumoto A, Fridovich I. New class of potent catalysts of O2.-dismutation. Mn(III) ortho- methoxyethylpyridyl- and di-ortho-methoxyethylimidazolylporphyrins. Dalton Trans. 2004 Jun 7;(11):1696-702.
Okado-Matsumoto A, Batinić-Haberle I, Fridovich I. Complementation of SOD-deficient Escherichia coli by manganese porphyrin mimics of superoxide dismutase activity. Free Radic Biol Med. 2004 Aug 1;37(3):401-10.
Okado-Matsumoto A, Fridovich I. Amyotrophic lateral sclerosis: a proposed mechanism. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9010-4.
Okado-Matsumoto A, Fridovich I. Assay of superoxide dismutase: cautions relevant to the use of cytochrome c, a sulfonated tetrazolium, and cyanide. Anal Biochem. 2001 Nov 15;298(2):337-42.
Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem. 2001 Oct19;276(42):38388-93.
Okado-Matsumoto A, Matsumoto A, Fujii J, Taniguchi N. Effect of cAMP on inducible nitric oxide synthase gene expression: its dual and cell-specific functions. Antioxid Redox Signal. 2000 Winter;2(4):631-42.
Okado-Matsumoto A, Fridovich I. The role of alpha,beta -dicarbonyl compounds in the toxicity of short chain sugars. J Biol Chem. 2000 Nov 10;275(45):34853-7.
Okado-Matsumoto A, Myint T, Fujii J, Taniguchi N. Gain in functions of mutant Cu,Zn-superoxide dismutases as a causative factor in familial amyotrophic lateral sclerosis: less reactive oxidant formation but high spontaneous aggregation and precipitation. Free Radic Res. 2000 Jul;33(1):65-73.
Okado-Matsumoto A, Matsumoto A, Fujii J, Taniguchi N. Peroxiredoxin IV is a secretable protein with heparin-binding properties under reduced conditions. J Biochem. 2000 Mar;127(3):493-501.
Hojo Y, Okado A, Kawazoe S, Mizutani T. In vivo singlet-oxygen generation in blood of chromium(VI)-treated mice: an electron spin resonance spin-trapping study. Biol Trace Elem Res. 2000 Jul;76(1):85-93.
Hojo Y, Okado A, Kawazoe S, Mizutani T. Direct evidence for in vivo hydroxyl radical generation in blood of mice after acute chromium(VI) intake: electron spin resonance spin-trapping investigation. Biol Trace Elem Res. 2000 Jul;76(1):75-84.
Matsumoto A, Okado A, Fujii T, Fujii J, Egashira M, Niikawa N, Taniguchi N. Cloning of the peroxiredoxin gene family in rats and characterization of the fourth member. FEBS Lett. 1999 Jan 29;443(3):246-50.
Kawasaki Y, Fujii J, Miyazawa N, Hoshi A, Okado A, Tano Y, Taniguchi N. Specific detections of the early process of the glycation reaction by fructose and glucose in diabetic rat lens. FEBS Lett. 1998 Dec 11;441(1):116-20.
Che W, Asahi M, Takahashi M, Kaneto H, Okado A, Higashiyama S, Taniguchi N. Selective induction of heparin-binding epidermal growth factor-like growth factor by methylglyoxal and 3-deoxyglucosone in rat aortic smooth muscle cells. The involvement of reactive oxygen species formation and a possible implication for atherogenesis in diabetes. J Biol Chem. 1997 Jul 18;272(29):18453-9.
Seo HG, Fujii J, Asahi M, Okado A, Fujiwara N, Taniguchi N. Roles of purine nucleotides and adenosine in enhancing NOS II gene expression in interleukin-1 beta-stimulated rat vascular smooth muscle cells. Free Radic Res. 1997 May;26(5):409-18.
Fujiwara N, Okado A, Seo HG, Fujii J, Kondo K, Taniguchi N. Quinazoline derivatives suppress nitric oxide production by macrophages through inhibition of NOS II gene expression. FEBS Lett. 1996 Oct 21;395(2-3):299-303.
Okado A, Kawasaki Y, Hasuike Y, Takahashi M, Teshima T, Fujii J, Taniguchi N. Induction of apoptotic cell death by methylglyoxal and 3-deoxyglucosone in macrophage-derived cell lines. Biochem Biophys Res Commun. 1996 Aug 5;225(1):219-24.
Fujii J, Myint T, Okado A, Kaneto H, Taniguchi N. Oxidative stress caused by glycation of Cu,Zn-superoxide dismutase and its effects on intracellular components. Nephrol Dial Transplant. 1996;11 Suppl 5:34-40.