Host: The Japanese Pharmacological Society
Name : The 97th Annual Meeting of the Japanese Pharmacological Society
Number : 97
Location : [in Japanese]
Date : December 14, 2023 - December 16, 2023
Amyotrophic lateral sclerosis (ALS) is a rare but devastating disease characterized by progressive neurodegeneration of motor neurons, leading to skeletal muscle denervation. Neuromuscular junction (NMJ) degeneration is an early pathological change in ALS. Nonetheless, the exact regulatory mechanisms and potential therapeutic interventions underlying this process remain largely unknown. Through our preliminary experiment using heterochronic parabiosis, a surgical technique enabling blood circulation sharing between organisms, we coupled ALS mice (SOD1G93A) with WT mice. Surprisingly, this led to NMJ shedding in the WT mice, a phenomenon not typically observed, thus hinting at the presence of NMJ-degenerating molecules in ALS mouse plasma. Next, we conducted an extensive analysis of cytokine levels in the plasma of SOD1G93A mice and WT mice and found markedly elevated levels of cytokine X in the ALS mice plasma, with abundant production originating from intestinal vascular endothelial cells. Treating SOD1G93A mice with neutralizing cytokine X antibodies significantly suppressed NMJ degeneration and improved sciatic compound muscle action potential (CMAP). Similarly, a comparable positive outcome was also observed with the treatment of lipid nanoparticles containing cytokine X receptor siRNA formulations in the skeletal muscle tissue of SOD1G93A mice. In addition to exploring the correlation between nervous system cell dysfunction within the lesion, our study unveiled a crucial role of systemically expressed cytokine X in ALS pathogenesis, offering valuable insights into a potential therapeutic biomarker for the disease.