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Parkinson's Disease and Related Disorders

開催日 2014/9/12
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Functional ESCRT machinery is required for the clearance of aggregate-prone proteins associated with neurodegenerative diseases

  • P2-299
  • 大嶋 龍司 / Ryuji Oshima:1,2 長谷川 隆文 / Takafumi Hasegawa:1 玉井 恵一 / Keiichi Tamai:2 菅野 直人 / Naoto Sugeno:1 三浦 永美子 / Emiko Miura:1 今野 昌俊 / Masatoshi Konno:1 菊池 昭夫 / Akio Kikuchi:1 武田 篤 / Atsushi Takeda:3 田中 伸幸 / Nobuyuki Tanaka:2 青木 正志 / Masashi Aoki:1 
  • 1:東北大学 大学院医学系研究科 神経内科学分野 / Dept of Neurol, Tohoku Univ Grad Sch of Med, Miyagi, Japan 2:宮城県立がんセンター / Miyagi Cancer Ctr Res Inst, Miyagi, Japan 3:仙台西多賀病院 / Natl Hosp Org Sendai-Nishitaga Hosp, Miyagi, Japan 

The aim of this study is to determine whether ESCRT (endosomal sorting complex required for transport) dysfunction is associated with the abnormal accumulation of protein aggregates and subsequent neurodegeneration in mammalian brain.The autophagy/lysosomal system plays an important role in the bulk-degradation of cytosolic constituents in lysosomes. Increasing evidence suggests that ESCRT system is implicated in autophagic clearance of aggregation-prone proteins associated with various neurodegenerative diseases. However, very little work has been undertaken to understand the mechanisms by which ESCRT machinery is involved in the pathogenic process leading to neurodegeneration. We specifically deleted the ESCRT-0 component, hepatocyte growth factor-regulated tyrosine kinase substrate (hrs), in neurons of the adult forebrain by using conditional knockout mice on calcium/ calmodulin-dependent protein kinase II alpha (CaMKII)-Cre-expressing background. The locomotor performance in the hrsflox/flox; CaMKII-Cre mice was significantly impaired compared to that in hrs+/+; CaMKII-Cre mice. Histological analysis showed the prominent neuronal cell loss in CA1/CA3 regions of the hippocampus. Furthermore, we observed the striking accumulation of the insoluble forms of α-synuclein, TDP-43, tau, and huntingtin as well as the ubiquitinated proteins and p62 in the brain of hrsflox/flox; CaMKII-Cre mice. These histopathological changes were accompanied by the increased expression of 8-OHdG and phospho-p38/SAPK. These findings suggest that the functional disruption of ESCRT machinery compromises autophagic/lysosomal degradation of aggregate-prone proteins and acquires cytotoxic activity leading to neuronal cell death.

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