Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
Elife. 2022 Nov 29;11:e74805. doi: 10.7554/eLife.74805.
A 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 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.
内质网（ER）应激与神经退行性疾病发展之间的因果关系仍存在争议。在这里，我们专注于 Seipinopathy，一种显性运动神经元疾病，基于其致病基因产物 Seipin 是一种跨内质网膜两次的蛋白质的发现。Seipin 的功能获得性突变产生非糖基化的 Seipin（ngSeipin），先前已表明其在细胞和小鼠水平上诱导 ER 应激和细胞凋亡，尽管其机制尚不清楚。我们发现，易于聚集的 ngSeipin 主要使内质网中的主要钙泵 SERCA2b 失活，并降低内质网中的钙浓度，导致人结直肠癌细胞（HCT116）中的 ER 应激和细胞凋亡。这种失活需要 ngSeipin 的寡聚化和 ngSeipin 的 C 末端与 SERCA2b 的直接相互作用，并且在表达 ngSeipin 的内质网缺乏神经母细胞瘤（SH-SY5Y）细胞中观察到。因此，我们的结果为上述争议提供了一个新的方向。
