title: Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases.
abstract: The deposition of amyloid-like filaments in the brain is the central event in the pathogenesis of neurodegenerative diseases. Here we report cellular models of intracytoplasmic inclusions of α-synuclein, generated by introducing nucleation seeds into SH-SY5Y cells with a transfection reagent. Upon introduction of preformed seeds into cells overexpressing α-synuclein, abundant, highly filamentous α-synuclein-positive inclusions, which are extensively phosphorylated and ubiquitinated and partially thioflavin-positive, were formed within the cells. SH-SY5Y cells that formed such inclusions underwent cell death, which was blocked by small molecular compounds that inhibit β-sheet formation. Similar seed-dependent aggregation was observed in cells expressing four-repeat Tau by introducing four-repeat Tau fibrils but not three-repeat Tau fibrils or α-synuclein fibrils. No aggregate formation was observed in cells overexpressing three-repeat Tau upon treatment with four-repeat Tau fibrils. Our cellular models thus provide evidence of nucleation-dependent and protein-specific polymerization of intracellular amyloid-like proteins in cultured cells.
authors.affiliation: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, USA. nonaka-tk@igakuken.or.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Sayuri T
authors.initials: ST
authors.lastname: Watanabe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D051844:alpha-Synuclein; D016875:tau Proteins
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