title: α-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly.
abstract: α-Synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that α-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric α-synuclein to promote microtubule assembly and the effects of conformational changes of α-synuclein on Tau-promoted microtubule assembly. In marked contrast to previous findings, monomeric α-synuclein had no effect on microtubule polymerization. However, both α-synuclein fibrils and protofibrils inhibited Tau-promoted microtubule assembly. The inhibitory effect of α-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin-down techniques revealed that α-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of α-synuclein and Tau, the acidic C-terminal region of α-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of α-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that α-synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells.
authors.affiliation: From the Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, the Department of Biological Science, Tokyo Metropolitan University, Tokyo 192-0397, and.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: From the Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.affiliation: From the Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, the Department of Neurology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi 305-8576, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Terada
authors.affiliation: the Department of Neurology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi 305-8576, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.affiliation: the Department of Biological Science, Tokyo Metropolitan University, Tokyo 192-0397, and.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hisanaga
authors.affiliation: From the Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, hasegawa-ms@igakuken.or.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D016631:Lewy Bodies / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D066329:Protein Aggregates; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D016875:tau Proteins
keywords: Tau protein (Tau); fibril; microtubule; protein misfolding; synuclein