Neuromyelitis optica (NMO)‐IgG‐driven organelle reorganization in human iPSC‐derived astrocytes

Neuromyelitis optica (NMO) is an autoimmune disease that primarily targets astrocytes. Autoantibodies (NMO-IgG) against the water channel protein, aquaporin 4 (AQP4), are a serologic marker in NMO patients, and they known to be responsible for pathophysiology of disease. In brain, AQP4 mainly expressed astrocytes, especially at end-feet, where form blood-brain barrier. Following interaction between NMO-IgG rapid endocytosis initiates pathogenesis. However, cellular molecular mechanisms astrocyte destruction by autoantibodies remain largely elusive. We established vitro human model system using induced pluripotent stem cells (iPSCs) technology combination with patient-derived serum IgG elucidate functional changes caused NMO-IgG. Herein, we observed induces structural alterations mitochondria their association endoplasmic reticulum (ER) lysosomes ultrastructural level, which potentially leads impaired mitochondrial functions dynamics. Indeed, astrocytes display bioenergetics autophagy activity presence further demonstrated NMO-IgG-driven ER membrane deformation into multilamellar structure Together, show rearranges organelles alter our iPSCs offers previously unavailable experimental opportunities study pathophysiological or conduct large-scale screening potential therapeutic compounds targeting astrocytic abnormalities patients NMO.