C9orf72 poly-GA proteins impair neuromuscular transmission

Wen-Yo Tu; Wentao Xu; Jianmin Zhang; Shuyuan Qi; Lei Bai; Chengyong Shen; Kejing Zhang

doi:10.24272/j.issn.2095-8137.2022.356

Volume 44 Issue 2

Mar. 2023

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Article Navigation > Zoological Research > 2023 > 44(2): 331-340

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

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C9orf72 poly-GA proteins impair neuromuscular transmission

doi: 10.24272/j.issn.2095-8137.2022.356

Wen-Yo Tu^{1, #},
Wentao Xu^{1, #},
Jianmin Zhang¹,
Shuyuan Qi¹,
Lei Bai¹,
Chengyong Shen^{1, 2
,
,},
Kejing Zhang^{1
,
,}

1.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Neurobiology, First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, China
2.
MOE Frontier Science, Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou, Zhejiang 310058, China

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.cn; kjzhang@zju.edu.cn
Received Date: 2022-12-14
Accepted Date: 2023-02-15

Published Online: 2023-02-17

Publish Date: 2023-03-18

Abstract

Abstract

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.
- Amyotrophic lateral sclerosis,
- Neuromuscular junction,
- Poly-Gly-Ala,
- Agrin

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References(66)

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