NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.

TitleNEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsMartin, PB, Kigoshi-Tansho, Y, Sher, RB, Ravenscroft, G, Stauffer, JE, Kumar, R, Yonashiro, R, Müller, T, Griffith, C, Allen, W, Pehlivan, D, Harel, T, Zenker, M, Howting, D, Schanze, D, Faqeih, EA, Almontashiri, NAM, Maroofian, R, Houlden, H, Mazaheri, N, Galehdari, H, Douglas, G, Posey, JE, Ryan, M, Lupski, JR, Laing, NG, Joazeiro, CAP, Cox, GA
JournalNat Commun
Volume11
Issue1
Pagination4625
Date Published2020 09 15
ISSN2041-1723
KeywordsAmino Acid Sequence, Animals, Female, Humans, Male, Mice, Mice, Knockout, Mutation, Neuromuscular Diseases, Proteolysis, Ribosomes, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment
Abstract

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

DOI10.1038/s41467-020-18327-6
PubMed ID32934225
PubMed Central IDPMC7494853
Grant ListR01 NS075719 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R01 NS102414 / NS / NINDS NIH HHS / United States