期刊
EMBO MOLECULAR MEDICINE
卷 11, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201809423
关键词
ALS; C9orf72; DPR; excitotoxicity; FTD
资金
- Strauss Foundation
- NIH [R21-NS090912, 4R00NS091486-03]
- Muscular Dystrophy Association
- Robert Packard Center for ALS Research
- Farber Family Foundation
Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2 alpha complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.
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