- 著者
-
Uemura Norihito
Koike Masato
Ansai Satoshi
Kinoshita Masato
Ishikawa-Fujiwara Tomoko
Matsui Hideaki
Naruse Kiyoshi
Sakamoto Naoaki
Uchiyama Yasuo
Todo Takeshi
Takeda Shunichi
Yamakado Hodaka
Takahashi Ryosuke
- 出版者
- Public Library of Science
- 雑誌
- PLOS genetics (ISSN:15537404)
- 巻号頁・発行日
- vol.11, no.4, 2015-04-02
- 被引用文献数
-
59
パーキンソン病の解明に役立つメダカの作製に成功 -メダカが神経変性疾患の研究に貢献できる可能性- 京都大学プレスリリース. 2015-04-09.Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (α-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of α-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of α-syn accumulation caused by GCase deficiency, and the minimal contribution of α-syn to the pathogenesis of neuronopathic GD.