Non-glycosylated Seipin to Cause a Motor Neuron Disease Induces ER stress and Apoptosis by Inactivating the ER Calcium Pump SERCA2b

ABSTRACTA causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a hairpin-like transmembrane protein in the ER. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis. This inactivation required oligomerization of ngSeipin and direct interaction of the ngSeipin C-terminus with SERCA2b, and was observed in Seipin-deficient human colorectal carcinoma-derived cells (HCT116) expressing ngSeipin at a level comparable with that in neuroblastoma cells (SH-SY5T). Our results thus provide a new direction to controversy noted above.