Astroglial ER protein Membralin is an essential neuroinflammation regulator

The endoplasmic reticulum (ER) is the primary organelle for synthesizing membrane proteins, secretory proteins, and lipids. Disturbance of ER homeostasis in peripheral immune cells is associated with inflammatory responses. Glial cells, including astrocytes and microglia, are the immune cells in the brains, becoming reactive/gliosis during the progression of Alzheimer's disease (AD). However, whether and how glial protein homeostasis mediate the reactive state of glial cells is yet to be investigated. We previously identified a novel ER-associated degradation component, membralin/TMEM259, as an important mediator in neurodegeneration. Loss of membralin impaired the turnover of nicastrin protein, which increased gamma-secretase complex formation and activity. Knockdown membralin in the TgCRND8-AD mice exaggerated beta-amyloid-associated neuronal damage. Moreover, selective deletion of membralin in astrocytes decreased excitatory amino acid transporter 2 (EAAT2) expression and induced excitotoxicity. Elevating membralin levels in SOD1 G93A ALS mouse model can significantly extend the lifespan of the animals.Transcriptomic profiles of the cortex tissues and histology were analyzed in the astrocyte-conditional membralin knockout animals. Primary astrocyte ER morphology was examined by electron microscopy analysis. We crossed the transgenic membralin animals with 5xFAD animals and assessed the AD pathology.Astroglial membralin knockout animals develop strong neuroinflammation phenotypes. Loss of membralin in astrocytes disrupts ER homeostasis and nuclear envelop integrity, and induces senescence-like phenotypes. In contrast, the elevation of membralin in astrocytes can alleviate the induction of C3+ astrocytes upon c1q/IL1a/TNFa treatment. Further, elevating membralin levels in 5XFAD mouse model can significantly reduce the AD pathologies.Membralin is critical in mediating the reactive states of astrocytes. Modulation of astroglial ER homeostasis can be a promising target to regulate neuroinflammation for AD therapy.