首页|C9orf72 poly-GA proteins impair neuromuscular transmission

C9orf72 poly-GA proteins impair neuromuscular transmission

扫码查看
原文链接
  • 万方数据
  • 维普
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 sclerosisNeuromuscular junctionPoly-Gly-AlaAgrin

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

展开 >

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

MOE Frontier Science,Center for Brain Research and Brain-Machine Integration,Zhejiang University,Hangzhou,Zhejiang 310058,China

National Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaZhejiang Provincial Natural Science FoundationNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

2022YFF10005002021YFA1101100LZ22C11000232271031822300383187120332071032

2023

10.24272/j.issn.2095-8137.2022.356

动物学研究
中国科学院昆明动物研究所 中国动物学会

动物学研究

CSTPCDCSCD
影响因子：0.582
ISSN：0254-5853
年,卷(期)：2023.44(2)
  • 66