C9orf72 poly-GA proteins impair neuromuscular transmission  

作　　者：Wen-Yo Tu Wentao Xu Jianmin Zhang Shuyuan Qi Lei Bai Chengyong Shen Kejing Zhang 

机构地区：[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

出　　处：《Zoological Research》2023年第2期331-340,共10页动物学研究（英文）

基　　金：supported by the National Key Research and Development Program of China (2022YFF1000500 to K.Z. and2021YFA1101100 to C.S.);Zhejiang Provincial Natural Science Foundation(LZ22C110002 to C.S.);National Natural Science Foundation of China(32271031 to K.Z. and 82230038, 31871203, and 32071032 to C.S.)。

摘　　要：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 G4C2repeat-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.

关 键 词：Amyotrophic lateral sclerosis Neuromuscular junction Poly-Gly-Ala AGRIN 

分 类 号：R744.8[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]