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Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. 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 in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above.<\/jats:p>","DOI":"10.7554\/elife.74805","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T04:15:10Z","timestamp":1667794510000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.74805","source":"Crossref","is-referenced-by-count":12,"title":["A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1331-811X","authenticated-orcid":true,"given":"Shunsuke","family":"Saito","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02kpeqv85","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biophysics, Graduate School of Science, Kyoto University","place":["Kyoto, 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