Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats

Author:

Tseng Yi-Ju12,Krans Amy13,Malik Indranil14,Deng Xiexiong5,Yildirim Evrim1,Ovunc Sinem1,Tank Elizabeth M H1,Jansen-West Karen6,Kaufhold Ross17,Gomez Nicolas B17,Sher Roger8,Petrucelli Leonard6,Barmada Sami J1,Todd Peter K13ORCID

Affiliation:

1. Department of Neurology, University of Michigan , Ann Arbor , MI  48109 , USA

2. Cellular and Molecular Biology Graduate Program, University of Michigan , Ann Arbor , MI  48109 , USA

3. Ann Arbor Veterans Administration Healthcare , Ann Arbor , MI  48109 , USA

4. Department of Biotechnology, Indian Institute of Technology Hyderabad , Kandi , Sangareddy, 502284   Telangana , India

5. Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institute, University of Michigan , Ann Arbor , MI  48109 , USA

6. Department of Neuroscience, Mayo Clinic , Jacksonville , FL  32224 , USA

7. Medical Scientist Training Program, University of Michigan , Ann Arbor , MI  48109 , USA

8. Department of Neurobiology and Behavior & Center for Nervous System Disorders, Stony Brook University , Stony Brook , NY  11794 , USA

Abstract

Abstract A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation—suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.

Funder

NIH

VA BLRD

Cellular and Molecular Biology Graduate Program, University of Michigan

Alzheimer's Association Research Fellowship

Publisher

Oxford University Press (OUP)

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3