Modification of tau by 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP): Effects of nitric oxide-linked chemical modification on tau aggregation

Jun Yoshitake, Yoshiyuki Soeda, Tomoaki Ida, Akio Sumioka, Misato Yoshikawa, Kenji Matsushita, Takaaki Akaike, Akihiko Takashima

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)22714-22720
ページ数7
ジャーナルJournal of Biological Chemistry
291
43
DOI
出版ステータスPublished - 2016 10 21

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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