Gain-of-toxic mutations in the N-glycosylation motif of the seipin/BSCL2 gene (namely, the N88S and S90L mutations) cause autosomal dominant motor neuron diseases, termed 'seipinopathy'. Expressed mutant seipin is improperly folded and accumulates in the endoplasmic reticulum (ER), leading to an unfolded protein response (UPR). Furthermore, cells expressing mutant seipin contain unique cytoplasmic inclusion bodies (IB) that form via a different mechanism from that of ubiquitinated inclusions, or aggresomes. Whether the formation of these IB is pathogenic or protective in neurodegenerative diseases remains unclear. Here, we determined that mutant seipin IB are negative for two well-established ER markers, immunoglobulin-heavy-chain-binding protein and calnexin, indicating a distinct compartmentalization from the main ER, and that mutant seipin IB are formed via a mechanism that is independent of major UPR transducers and ER chaperons. Electron microscopy and coexpression study with variant α1-antitrypsin cDNA showed that seipin IB are compatible with unique cytoplasmic vesicles known as ER-derived protective organelles (ERPO). We also obtained evidence that seipin IB exhibit a cytoprotective property via the attenuation of ER stress. These findings suggest that ERPO, such as seipin IB, are a novel adaptation machinery against the accumulation of unfolded proteins in the ER.
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