期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 8, 页码 730-742出版社
WILEY-BLACKWELL
DOI: 10.1002/emmm.201100995
关键词
alternative splicing; Alzheimer's disease; cholinergic signalling; hnRNP; RNA
资金
- Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation [1799/10]
- European community's network for Excellence Grant [LSH-2004-1.1.5-3]
- German Israeli Foundation
- Gatsby foundation
- RoseTrees foundation
- Affymetrix early technological access program
- Levi Eshkol fellowships
Genetic studies link inherited errors in RNA metabolism to familial neurodegenerative disease. Here, we report such errors and the underlying mechanism in sporadic Alzheimer's disease (AD). AD entorhinal cortices presented globally impaired exon exclusions and selective loss of the hnRNP A/B splicing factors. Supporting functional relevance, hnRNP A/B knockdown induced alternative splicing impairments and dendrite loss in primary neurons, and memory and electrocorticographic impairments in mice. Transgenic mice with disease-associated mutations in APP or Tau displayed no alterations in hnRNP A/B suggesting that its loss in AD is independent of A beta and Tau toxicity. However, cholinergic excitation increased hnRNP A/B levels while in vivo neurotoxin-mediated destruction of cholinergic neurons caused cortical AD-like decrease in hnRNP A/B and recapitulated the alternative splicing pattern of AD patients. Our findings present cholinergic-mediated hnRNP A/B loss and impaired RNA metabolism as important mechanisms involved in AD.
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