期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 23, 页码 6640-6652出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv369
关键词
-
资金
- BBSRC/Lilly
- Parkinson's UK [G-1404]
- Academy of Finland
- Sigrid Juselius Foundation
- FishMed/EU Seventh Framework Programme [316125]
- Wellcome Trust/MRC [WT089698]
- National Institute for Environmental Health Sciences [ES022644]
- Australian NHMRC C.J. Martin fellowship [GNT1054664]
- MRC Programme Grant (SAR) [MR/M004864/1]
- MRC Center [G0700091]
- University of Sheffield Vice-Chancellor's Fellowship
- Wellcome Trust [GR077544AIA]
- Parkinson's UK
- MRC [MR/M004864/1, G0701932, G108/595] Funding Source: UKRI
- Medical Research Council [MR/M004864/1, G0701932, G108/595, G0700091B] Funding Source: researchfish
- Parkinson's UK [G-1404, G-1007] Funding Source: researchfish
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1c.1276_1298del mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1c.1276_1298del zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据