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演題詳細

Symposium

蛋白質・オルガネラ品質管理病としてのパーキンソン病
Disruption of quality control system of protein/organella and Parkinson's diseases

開催日 2014/9/13
時間 17:10 - 19:10
会場 Room E(301)
Chairperson(s) 今居 譲 / Yuzuru Imai (順天堂大学大学院医学研究科 / Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Japan)
長谷川 隆文 / Takafumi Hasegawa (東北大学大学院医学系研究科 / Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Japan)


The role of protein aggregation in pathogenesis and spread of neurodegenerative disease

  • S3-E-3-5
  • Ron R. Kopito: 
  • 1:Department of Biology, Stanford University, USA / Department of Biology, Stanford University, USA 

Pathognomonic accumulation of ubiquitin (Ub) conjugates in human neurodegenerative diseases such as Huntington’s disease has suggested the hypothesis that highly aggregated pathogenic proteins non-competitively interfere with 26S proteasome (26S) activity. We have explored possible mechanisms by which an N-terminal fragment of mutant huntingtin (N-htt) might inhibit 26S function. Exploiting a cell-free system using purified components we show that ubiquitinated N-htt -whether aggregated or not- does not choke or clog 26S. Quantitative flow-cytometry analysis shows that both Ub-dependent and Ub-independent proteasome reporters accumulate in cells when the cytoplasmic concentration of mutant N-htt exceeds a threshold above which its solubility can no longer be maintained, indicating that stabilization of 26S substrates is linked to N-htt aggregation and not to impaired function of Ub conjugation pathways. Single-cell time lapse image analysis shows that above its critical intracellular concentration, mutant N-htt becomes rapidly recruited to cytoplasmic inclusions that are initially devoid of Ub, and that UPS reporters accumulate, only in a small fraction of surviving cells, and only after a considerable lag . Although synthetically polyubiquitinated N-htt can compete with other Ub conjugates for access to 26S in vitro, quantitative mass spectrometry establishes that the vast majority of mutant N-htt in cells is not conjugated to Ub. Our data confirm that proteasomes are not directly impaired by aggregated N-terminal fragments of htt and instead suggest a model which links Ub accumulation to impaired function of the cellular proteostasis network.

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