2008年2月
Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic
HUMAN MOLECULAR GENETICS
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- 巻
- 17
- 号
- 3
- 開始ページ
- 345
- 終了ページ
- 356
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1093/hmg/ddm311
- 出版者・発行元
- OXFORD UNIV PRESS
Expanded polyglutamine (polyQ) repeats cause neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. Although soluble polyQ oligomers have been proposed as a cytotoxic structure, the cytotoxicity of soluble polyQ oligomers, not inclusion bodies (IBs), has not been proven in living cells. To clarify the cytotoxicity of soluble polyQ oligomers, we carried our fluorescence resonance energy transfer (FRET) confocal microscopy and distinguished oligomers from monomers and IBs in a single living cell. FRET signals were detected when donor and acceptor fluorescent proteins were attached to the same side, not the opposite side, of polyQ repeats, which agrees with a parallel beta-sheet or a head-to-tail cylindrical beta-sheet model. These FRET signals disappeared in semi-intact cells, indicating that these polyQ oligomers are soluble. PolyQ monomers assembled into soluble oligomers in a length-dependent manner, which was followed by the formation of IBs. Notably, survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with IBs or monomers. These results indicate that a length-dependent formation of oligomers is an essential mechanism underlying neurodegeneration in polyQ-mediated disorders.
- リンク情報
- ID情報
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- DOI : 10.1093/hmg/ddm311
- ISSN : 0964-6906
- PubMed ID : 17947294
- Web of Science ID : WOS:000252544000002