On May 11, the Li Lei Research Group of the School of Life Science and Technology of Shanghai University of Science and Technology published a research paper entitled "The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice" in the international academic journal Molecular Therapy (Molecular Therapy). It reported a new mechanism of neuromuscular junction damage in ALS and found a new strategy for treatment.

Amyotrophic lateral sclerosis (ALS), also known as ALS, is a life-threatening disease of the motor nervous system. Due to the degeneration and death of upper and lower motoneurons, patients lead to muscle weakness, paralysis and atrophy, and finally respiratory muscle dyspnea resulting in death. Unfortunately, there is no effective treatment for the disease, and patients often die within 3-5 years of diagnosis. 

The main function of motoneurons, especially the lower motoneurons located in the spinal cord, is to transmit signals to muscles and control muscle contraction. The structure responsible for transmitting motor neuron signals to the muscle is called the neuromuscular junction. The abnormality of the structure and function of neuromuscular junction is the main cause of the loss of motor function in patients with ALS. The dysfunction of neuromuscular junction occurs in the early stage of ALS disease, much earlier than the death of motor neurons. However, the cause of neuromuscular junction dysfunction in patients with ALS is unclear.

Fig. 1. Neuromuscular junction dysfunction occurs in the early stage of ALS, which leads to muscle atrophy and nerve degeneration.

In this work, we found that in the C9orf72-ALS mouse model, motoneurons secrete poly-PR protein to inhibit the continuous activation of MuSK signals maintained by the neuromuscular junction, resulting in abnormal structure and function of the neuromuscular junction. Injection of MuSK-activated monoclonal antibody into ALS mouse model can improve the structure and function of neuromuscular junction, improve animal motor ability and prolong animal survival time, showing the potential of MuSK antibody as a new strategy for ALS treatment. As the abnormal function of neuromuscular junction, especially muscle denervation is the early manifestation of all ALS patients, this treatment strategy is expected to have application potential in many ALS patients.

Fig. 2. Schematic diagram of MuSK antibody improving phenotype of C9orf72-ALS mouse model.

The first authors are Sun Shuangshuang and Shen Yihui, doctoral students of Li Lei's research group of Shanghai University of Science and Technology, Li Lei of Shanghai University of Science and Technology and Zhang Qijie of the first affiliated Hospital of Fujian Medical University. Shanghai University of Science and Technology is the first completion unit and communication unit.

Article link：https://doi.org/10.1016/j.ymthe.2024.05.016