title: Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties.
abstract: Tauopathies are neurodegenerative diseases in which insoluble fibrillar aggregates of a microtubule-binding protein, Tau, are abnormally accumulated. Pathological Tau fibrils often exhibit structural polymorphisms that differ among phenotypically distinct tauopathies; however, a molecular mechanism to generate polymorphic Tau fibrils remains obscure. Here, we note the formation of a disulfide bond in isoforms of full-length Tau and show that the thiol-disulfide status as well as the isoform composition determines structural and morphological properties of Tau fibrils in vitro. Mainly two regions in a Tau primary sequence are found to act as structural blocks for building a protease-resistant core of Tau fibrils. Interactions among those two blocks for building a core structure depend upon the thiol-disulfide status in each isoform of Tau, which results in the formation of polymorphic fibrils with distinct structural properties. Furthermore, we have found that more diverse structures of Tau fibrils emerge through a cross-seeded fibrillation between heterologous pairs of Tau isoforms. We thus propose that isoform- and disulfide-dependent combinatorial interactions among multiple regions in a Tau sequence endow Tau fibrils with various structures, i.e. polymorphism.
authors.affiliation: Department of Chemistry, Keio University, Yokohama, Kanagawa 223-8522, Japan. furukawa@chem.keio.ac.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Kumi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D004220:Disulfides / Q000378:metabolism*; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004220:Disulfides; D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins