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

Paige B. Martin, Yu Kigoshi-Tansho, Roger B. Sher, Gianina Ravenscroft, Jennifer E. Stauffer, Rajesh Kumar, Ryo Yonashiro, Tina Müller, Christopher Griffith, William Allen, Davut Pehlivan, Tamar Harel, Martin Zenker, Denise Howting, Denny Schanze, Eissa A. Faqeih, Naif A. M. Almontashiri, Reza Maroofian, Henry Houlden, Neda Mazaheri, Hamid Galehdari, Ganka Douglas, Jennifer E. Posey, Monique Ryan, James R. Lupski, Nigel G. Laing, Claudio A. P. Joazeiro () and Gregory A. Cox ()
Additional contact information
Paige B. Martin: The Jackson Laboratory
Yu Kigoshi-Tansho: Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
Roger B. Sher: Stony Brook University
Gianina Ravenscroft: University of Western Australia
Jennifer E. Stauffer: The Jackson Laboratory
Rajesh Kumar: Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
Ryo Yonashiro: Scripps Research
Tina Müller: Scripps Research
Christopher Griffith: University of South Florida
William Allen: Mission Health
Davut Pehlivan: Baylor College of Medicine
Tamar Harel: Hadassah-Hebrew University Medical Center
Martin Zenker: Otto-von-Guericke University Magdeburg
Denise Howting: University of Western Australia
Denny Schanze: Otto-von-Guericke University Magdeburg
Eissa A. Faqeih: King Fahad Medical City
Naif A. M. Almontashiri: Taibah University
Reza Maroofian: UCL Queen Square Institute of Neurology
Henry Houlden: UCL Queen Square Institute of Neurology
Neda Mazaheri: Shahid Chamran University of Ahvaz
Hamid Galehdari: Shahid Chamran University of Ahvaz
Ganka Douglas: GeneDx, Inc
Jennifer E. Posey: Baylor College of Medicine
Monique Ryan: The Royal Children’s Hospital
James R. Lupski: Baylor College of Medicine
Nigel G. Laing: University of Western Australia
Claudio A. P. Joazeiro: Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
Gregory A. Cox: The Jackson Laboratory

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18327-6

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