NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease
| Autor: | Christopher C. Griffith, Martin Zenker, William E. Allen, Ganka Douglas, Denise Howting, Eissa Faqeih, Roger B. Sher, Davut Pehlivan, Nigel G. Laing, Henry Houlden, Jennifer E. Stauffer, Naif A.M. Almontashiri, Hamid Galehdari, Paige B. Martin, Ryo Yonashiro, Rajesh Kumar, Tamar Harel, Yu Kigoshi-Tansho, Gregory A. Cox, James R. Lupski, Reza Maroofian, Monique M. Ryan, Gianina Ravenscroft, Neda Mazaheri, Jennifer E. Posey, Tina Müller, Claudio A. P. Joazeiro, Denny Schanze |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Neuromuscular disease Saccharomyces cerevisiae Proteins Science General Physics and Astronomy Saccharomyces cerevisiae Protein degradation medicine.disease_cause Ribosome General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine RQC complex medicine Animals Humans Amino Acid Sequence Neurodegeneration Author Correction lcsh:Science Mice Knockout Mutation Multidisciplinary biology Disease genetics RNA-Binding Proteins Translation (biology) General Chemistry Neuromuscular Diseases medicine.disease Cell biology Ubiquitin ligase 030104 developmental biology Mechanisms of disease Proteolysis biology.protein Female lcsh:Q Ribosomes Sequence Alignment 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families. |
| Databáze: | OpenAIRE |
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