期刊
BRAIN
卷 140, 期 -, 页码 887-897出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx024
关键词
C9ALS/FTD; C9orf72; RAB7L1; extracellular vesicles; haploinsufficiency
资金
- Uehara Memorial Foundation
- MRC Confidence in Concept award
- John Fell Fund award
- MND Association
- Netherlands Organization for Scientific Research (NWO)
- Japan Agency for Medical Research and Development (AMED) [16ek0109154h0002, 16am0301021h0002]
- Swedish Research council (VR-Med)
- Swedish Research council (EuroNanomed)
- Swedish Society of Medical Research (SSMF)
- MRC [MR/L002167/1, MR/K01014X/1, MC_PC_13073] Funding Source: UKRI
- Medical Research Council [MC_PC_13073] Funding Source: researchfish
- Motor Neurone Disease Association [Talbot/Oct16/889-792, Talbot/July13/820-791, Talbot-Mutihac/Apr15/832-791] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15H01198, 15K07039, 17H05682, 15J11847, 15K19018, 15H04367] Funding Source: KAKEN
A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells. The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional transGolgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. Genetic ablation of RAB7L1or C9orf72 in SH-SY5Y cells recapitulated the findings in C9ALS/FTD fibroblasts and induced pluripotent stem cell neurons. When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss-and gain-of-function mechanisms play a role in disease pathogenesis. In conclusion, we have identified a novel mechanism for C9ALS/FTD pathogenesis highlighting the molecular regulation of intracellular and extracellular vesicle trafficking as an important pathway in C9ALS/FTD pathogenesis.
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