TY - JOUR
T1 - NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease
AU - Martin, Paige B.
AU - Kigoshi-Tansho, Yu
AU - Sher, Roger B.
AU - Ravenscroft, Gianina
AU - Stauffer, Jennifer E.
AU - Kumar, Rajesh
AU - Yonashiro, Ryo
AU - Müller, Tina
AU - Griffith, Christopher
AU - Allen, William
AU - Pehlivan, Davut
AU - Haral, Tamar
AU - Zenker, Martin
AU - Howting, Denise
AU - Schanze, Denny
AU - Faqeih, Eissa A.
AU - Almontashiri, Naif A.M.
AU - Maroofian, Reza
AU - Houlden, Henry
AU - Mazaheri, Neda
AU - Galehdari, Hamid
AU - Douglas, Ganka
AU - Posey, Jennifer E.
AU - Ryan, Monique
AU - Lupski, James R.
AU - Laing, Nigel G.
AU - Joazeiro, Claudio A.P.
AU - Cox, Gregory A.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85091051994
U2 - 10.1038/s41467-020-18327-6
DO - 10.1038/s41467-020-18327-6
M3 - Article
C2 - 32934225
AN - SCOPUS:85091051994
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4625
ER -