title: Prolonged nitric oxide treatment induces tau aggregation in SH-SY5Y cells.
abstract: Presence of cytoplasmic tau aggregates is a hallmark of brains in patients with tauopathies such as Alzheimer's disease. However, the mechanism underlying formation of these insoluble tau aggregates remains elusive. In this study, we investigated the impact of prolonged nitric oxide (NO) exposure on neuronal SH-SY5Y cells overexpressing human tau. Treatment with the NO donor DETA NONOate for up to 48h resulted in an increase in S-nitrosation of cellular proteins, inactivation of proteasome, and impairment of respiration. Western blot analysis of Triton X-soluble fractions of NO-treated cells revealed that persistent NO treatment increased heterogeneity in tau molecule size, as a result of dephosphorylation, and induced the formation of sodium dodecyl sulfate (SDS)-stable oligomeric tau aggregates, stabilized by disulfide bonds. Moreover, further NO treatment induced the formation of SDS-stable insoluble tau mega-aggregates that were composed of dephosphorylated full-length tau molecules and other proteins, and were stabilized through disulfide bonds. Evaluation of the role of these tau aggregates as potential seeds for tau fibrillization and elucidation of their formation mechanism in our model, could lead to better understanding of the pathogenesis of tauopathies.
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yo
authors.initials: Y
authors.lastname: Chin
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Watanabe
authors.forename: Takao
authors.initials: T
authors.lastname: Arai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D015538:Nitrosation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D024801:Tauopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D009569:Nitric Oxide