title: Pathological concentration of zinc dramatically accelerates abnormal aggregation of full-length human Tau and thereby significantly increases Tau toxicity in neuronal cells.
abstract: A pathological hallmark of Alzheimer disease and other tauopathies is the formation of neurofibrillary tangles mainly composed of bundles of fibrils formed by microtubule-associated protein Tau. Here we study the effects of Zn2+on abnormal aggregation and cytotoxicity of a pathological mutant ΔK280 of full-length human Tau. As revealed by Congo red binding assays, transmission electron microscopy, immunofluorescence, Western blot, and immunogold electron microscopy, pathological concentration of Zn2+dramatically accelerates the fibrillization of ΔK280 both in vitro and in SH-SY5Y neuroblastoma cells. As evidenced by annexin V-FITC apoptosis detection assay and MTT reduction assay, pathological concentration of Zn2+remarkably enhances ΔK280 fibrillization-induced apoptosis and toxicity in SH-SY5Y cells. Substitution of Cys-291 and Cys-322 with Ala, however, essentially eliminates such enhancing effects of Zn2+on the fibrillization and the consequent cytotoxicity of ΔK280. Furthermore, Zn2+is co-localized with and highly enriched in amyloid fibrils formed by ΔK280 in SH-SY5Y cells. The results from isothermal titration calorimetry show that Zn2+binds to full-length human Tau by interacting with Cys-291 and Cys-322, forming a 1:1 Zn2+-Tau complex. Our data demonstrate that zinc dramatically accelerates abnormal aggregation of human Tau and significantly increases Tau toxicity in neuronal cells mainly via bridging Cys-291 and Cys-322. Our findings could explain how pathological zinc regulates Tau aggregation and toxicity associated with Alzheimer disease.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: De-Lin
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xue-Shou
authors.initials: XS
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Du
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: liangyi@whu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002413:Cations, Divalent; D066329:Protein Aggregates; D016875:tau Proteins; D015032:Zinc
keywords: Alzheimer disease; Protein aggregation; Tau protein; Tau toxicity; Zinc