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演題詳細

Oral

パーキンソン病とその類縁疾患 1
Parkinson's Disease and Related Disorders 1

開催日 2014/9/12
時間 17:10 - 18:10
会場 Room I(311+312)
Chairperson(s) 小澤 健太郎 / Kentaro Ozawa (奈良県立医科大学 / Nara Medical University, Japan)
山門 穂高 / Hodaka Yamakado (京都大学大学院医学研究科 臨床神経学  / Department of Neurology, Kyoto University Graduate School of Medicine, Japan)

ゴーシェ病モデルメダカにおけるアルファシヌクレインの蓄積は神経変性に寄与しない
Alpha-synuclein accumulation in Gaucher disease model of medaka does not contribute to neurodegeneration

  • O2-I-5-4
  • 上村 紀仁 / Norihito Uemura:1 藤原-石川 智子 / Tomoko Fujiwara-Ishikawa:2 木下 政人 / Masato Kinoshita:3 小池 正人 / Masato Koike:6 松井 秀彰 / Hideaki Matsui:5 山門 穂高 / Hodaka Yamakado:1 内山 安男 / Yasuo Uchiyama:6 藤堂 剛 / Takeshi Todo:2 武田 俊一 / Shun-ichi Takeda:4 髙橋 良輔 / Ryosuke Takahashi:1 
  • 1:京都大院医臨床神経 / Dept Neurol, Univ of Kyoto, Kyoto, Japan 2:大阪大院医放射線基礎医学 / Dept RadBio, Univ of Osaka, Suita, Japan 3:京都大院農応用生物科学専攻海洋生物機能学分野 / Division of Applied Biosciences, Univ of Kyoto, Kyoto, Japan 4:京都大院医放射線遺伝学 / Dept of Radiation Genetics, Univ of Kyoto, Kyoto, Japan 5:宮崎大学医学部機能制御学講座統合生理学分野 / Dept Medical Sciences, Section of Integrative Physiology Faculty of Medicine, Med Univ of Miyazaki, Miyaza 6:順天堂大学大学院医学研究科神経機能構造学 / Dept Cell Biology and Neuroscience, Univ of Juntendo, Tokyo, Japan 

Objective; To investigate how glucocerebrosidase (GBA) mutation causes Parkinson disease (PD), we generated GBA mutant medaka and analyzed its phenotype.

Background; GBA is a causative gene of Gaucher disease (GD), a lysosomal storage disease. Recent genetic studies have revealed that GBA mutation is a strong risk factor for sporadic PD. However, the underlying mechanisms remain unclear.

Methods; We generated GBA mutant medaka by screening a TILLING (Targeting Induced Local Lesions In Genomes) library. We also generated alpha-synuclein deletion mutant medaka by TALENs.

Results; We generated GBA nonsense mutant (GBA-/-) medaka completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death of human and mice lacking GCase activity, GBA-/- medaka survived for months, enabling us to analyze disease progression. GBA-/- medaka displayed non-selective neuronal cell death accompanied by neuroinflammation, lysosomal abnormalities and spheroids containing autophagosomes and alpha-synuclein accumulation. Unexpectedly, disruption of alpha-synuclein did not improve neuronal cell death nor neuroinflammation in GBA-/- medaka. Consistent with the findings of GBA-/- medaka, lysosomal inihibition of primary neurons from mouse embryos caused both LC3 and alpha-synuclein-positive puncta in axons.

Conclusion; glucocerebrosidase deficiency caused alpha-synuclein accumulation in degenerated axons through the impairment of autophagy-lysosome pathway, which does not contribute to neurodegeneration and neuroinflamation in GBA deficient model.

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