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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)

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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