Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.
Neurofibrillar tangles caused by intracellular hyperphosphorylated tau inclusion and extracellular amyloid β peptide deposition are hallmarks of Alzheimer's disease. Tau contains one or two cysteine residues in three or four repeats of the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) acts as a novel second messenger of nitric oxide (NO) by covalently binding cGMP to cysteine residues by electrophilic properties, a process termed protein S-guanylation. Here we studied S-guanylation of tau and its effects on tau aggregation. 8-Nitro-cGMP exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation in a thioflavin T assay. Atomic force microscopy observations indicated that S-guanylated tau could not form tau granules and fibrils. Further biochemical analyses showed that S-guanylated tau was inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP treatment significantly reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation, and therefore, increasing 8-nitro-cGMP levels in the brain could become a potential therapeutic strategy for Alzheimer's disease.
From the Departments of Aging Neurobiology and.|Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan.
Jun
J
Yoshitake
From the Departments of Aging Neurobiology and.
Yoshiyuki
Y
Soeda
the Department of Environmental Health Science and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan, and.
Tomoaki
T
Ida
the Department of Life Science, Gakushuin University Graduate School of Science, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
Akio
A
Sumioka
From the Departments of Aging Neurobiology and.
Misato
M
Yoshikawa
Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan.
Kenji
K
Matsushita
the Department of Environmental Health Science and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan, and.
Takaaki
T
Akaike
the Department of Life Science, Gakushuin University Graduate School of Science, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan 20160021@gakushuin.ac.jp.
Akihiko
A
Takashima
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D066329:Protein Aggregates; D011499:Protein Processing, Post-Translational; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D066329:Protein Aggregates; D016875:tau Proteins; D009569:Nitric Oxide; D006152:Cyclic GMP
8-nitro-cGMP; Alzheimer disease; S-guanylation; Tau protein (Tau); chemical modification; cysteine modification; oxidative stress; protein aggregation; tauopathy