Volume 44 Issue 2
Mar.  2023
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Wen-Yo Tu, Wentao Xu, Jianmin Zhang, Shuyuan Qi, Lei Bai, Chengyong Shen, Kejing Zhang. C9orf72 poly-GA proteins impair neuromuscular transmission. Zoological Research, 2023, 44(2): 331-340. doi: 10.24272/j.issn.2095-8137.2022.356
Citation: Wen-Yo Tu, Wentao Xu, Jianmin Zhang, Shuyuan Qi, Lei Bai, Chengyong Shen, Kejing Zhang. C9orf72 poly-GA proteins impair neuromuscular transmission. Zoological Research, 2023, 44(2): 331-340. doi: 10.24272/j.issn.2095-8137.2022.356

C9orf72 poly-GA proteins impair neuromuscular transmission

doi: 10.24272/j.issn.2095-8137.2022.356
Supplementary data to this article can be found online.
The authors declare that they have no competing interests.
K.Z. and C.S.: Conceptualization, supervision, resources, and writing. W.Y.T. and W.X.: Methodology, investigation, and writing. J.Z., S.Q., and L.B.: Investigation. All authors read and approved the final version of the manuscript.
#Authors contributed equally to this work
Funds:  This work was supported by the National Key Research and Development Program of China (2022YFF1000500 to K.Z. and 2021YFA1101100 to C.S.), Zhejiang Provincial Natural Science Foundation (LZ22C110002 to C.S.), and National Natural Science Foundation of China (32271031 to K.Z. and 82230038, 31871203, and 32071032 to C.S.)
More Information
  • Corresponding author: E-mail: cshen@zju.edu.cnkjzhang@zju.edu.cn
  • Received Date: 2022-12-14
  • Accepted Date: 2023-02-15
  • Published Online: 2023-02-17
  • Publish Date: 2023-03-18
  • Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular junctions (NMJs) occurs at the initial stage of ALS. Dipeptide repeat proteins (DPRs) from G4C2 repeat-associated non-ATG (RAN) translation are known to cause C9orf72-associated ALS (C9-ALS). However, DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients, indicating that DPRs may exert cell non-autonomous effects, in addition to the known intracellular pathological mechanisms. Here, we report that poly-GA, the most abundant form of DPR in C9-ALS, is released from cells. Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission in vivo. The NMJ structure cannot be maintained, as evidenced by the fragmentation of postsynaptic acetylcholine receptor (AChR) clusters and distortion of presynaptic nerve terminals. Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling. Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS. Thus, targeting NMJs could be an early therapeutic intervention for C9-ALS.
  • Supplementary data to this article can be found online.
    The authors declare that they have no competing interests.
    K.Z. and C.S.: Conceptualization, supervision, resources, and writing. W.Y.T. and W.X.: Methodology, investigation, and writing. J.Z., S.Q., and L.B.: Investigation. All authors read and approved the final version of the manuscript.
    #Authors contributed equally to this work
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