Seeded Aggregation and Toxicity of α-Synuclein and Tau: CELLULAR MODELS OF NEURODEGENERATIVE DISEASES* |
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Authors: | Takashi Nonaka Sayuri T Watanabe Takeshi Iwatsubo Masato Hasegawa |
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Institution: | From the ‡Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585 and ;the §Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Science, and ;¶Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan |
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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. |
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Keywords: | Alzheimer Disease Cell Death Parkinson Disease Proteasome Tau alpha-Synuclein |
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