Martin, PB;
Kigoshi-Tansho, Y;
Sher, RB;
Ravenscroft, G;
Stauffer, JE;
Kumar, R;
Yonashiro, R;
Müller, T;
Griffith, C;
Allen, W;
et al.
Martin, 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
(2020)
NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.
Nat Commun, 11 (1).
p. 4625.
ISSN 2041-1723
https://doi.org/10.1038/s41467-020-18327-6
SGUL Authors: Maroofian, Reza
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.
Item Type: |
Article
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Additional Information: |
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2020
Correction available at https://doi.org/10.1038/s41467-020-18941-4 |
Keywords: |
MD Multidisciplinary |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Nat Commun |
ISSN: |
2041-1723 |
Language: |
eng |
Dates: |
Date | Event |
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15 September 2020 | Published | 11 August 2020 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
Project ID | Funder | Funder ID |
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R01 NS102414 | NINDS NIH HHS | UNSPECIFIED | R01 NS075719 | NINDS NIH HHS | UNSPECIFIED | R35 NS105078 | NINDS NIH HHS | UNSPECIFIED | UM1 HG006542 | NHGRI NIH HHS | UNSPECIFIED | K08 HG008986 | NHGRI NIH HHS | UNSPECIFIED |
|
PubMed ID: |
32934225 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112430 |
Publisher's version: |
https://doi.org/10.1038/s41467-020-18327-6 |
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