title: Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study.
abstract: In many neurodegenerative diseases, formation of protein fibrillar aggregates has been observed as a major pathological change. Neurofibrillary tangles, mainly composed of fibrils formed by the microtubule-associated protein; Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer's disease. Tau belongs to the class of natively unfolded proteins and partially folds into an ordered β-structure during aggregation. Polyanionic cofactors such as heparin are commonly used as inducer of Tau aggregation in vitro. The role of heparin in nucleation and elongation steps during Tau fibril formation is not fully understood. In the current study, aggregation kinetics as well as structure of Tau amyloid fibrils, by using the 1N4R isoform, have been reproducibly determined in the presence of heparin and the shorter molecule; enoxaparin. The kinetic studies demonstrated that heparin (not enoxaparin) efficiently accelerates Tau amyloid formation and revealed, mechanistically, that the molecular weight of the inducer is important in accelerating amyloidogenesis. The kinetic parameter values of Tau amyloid aggregation, especially, the amyloid aggregation extent, were relatively different in the presence of heparin and enoxaparin, at various stoichiometries of the inducers binding. Also, based on the results, obtained from CD, FTIR, AFM and XRD studies, it may be suggested that the inducer length plays a critical role mainly in the nucleation process, so that it determines that oligomers lie on or off the pathway of Tau fibrillization. The biochemical results herein suggest that the chemical environment of the extracellular matrix as well as localization of distinct glycosaminoglycans may influence deposition behavior of Tau amyloidosis.
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Jangholi
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ashrafi-Kooshk
authors.affiliation: Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Seyed Shahriar
authors.initials: SS
authors.lastname: Arab
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Gholamhossein
authors.initials: G
authors.lastname: Riazi
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Farzad
authors.initials: F
authors.lastname: Mokhtari
authors.affiliation: Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mansour
authors.initials: M
authors.lastname: Poorebrahim
authors.affiliation: Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mahdiuni
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 33, bld. 2 Leninsky Ave., Moscow 119071, Russia.
authors.forename: Boris I
authors.initials: BI
authors.lastname: Kurganov
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Moosavi-Movahedi
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address: rkhodarahmi@mbrc.ac.ir.
authors.forename: Reza
authors.initials: R
authors.lastname: Khodarahmi
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000838:Anions; D052160:Benzothiazoles; D002942:Circular Dichroism; D018076:DNA, Complementary / Q000378:metabolism; D017984:Enoxaparin / Q000737:chemistry; D006025:Glycosaminoglycans / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008968:Molecular Conformation; D008970:Molecular Weight; D011489:Protein Denaturation; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles / Q000737:chemistry; D014466:Ultraviolet Rays; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000682:Amyloid; D000838:Anions; D052160:Benzothiazoles; D018076:DNA, Complementary; D017984:Enoxaparin; D006025:Glycosaminoglycans; C054369:MAPT protein, human; D020033:Protein Isoforms; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; D006493:Heparin
keywords: 1N4R Tau isoform; Amyloid aggregation; Enoxaparin; Heparin