Vapore Valentina, Mazzaglia Corrado, Sibilia Diego, Del Vecchio Mara, Fruhmann Gernot, Valenti Marta, Miranda Elena, Rinaldi Teresa, Winderickx Joris, Mazzoni Cristina
Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, 00185 Rome, Italy.
Functional Biology, KU Leuven, 3000 Leuven, Belgium.
Microorganisms. 2021 Jul 13;9(7):1498. doi: 10.3390/microorganisms9071498.
FENIB (familial encephalopathy with neuroserpin inclusion bodies) is a human monogenic disease caused by point mutations in the gene, characterized by the intracellular deposition of polymers of neuroserpin (NS), which leads to proteotoxicity and cell death. Despite the different cell and animal models developed thus far, the exact mechanism of cell toxicity elicited by NS polymers remains unclear. Here, we report that human wild-type NS and the polymerogenic variant G392E NS form protein aggregates mainly localized within the endoplasmic reticulum (ER) when expressed in the yeast . The expression of NS in yeast delayed the exit from the lag phase, suggesting that NS inclusions cause cellular stress. The cells also showed a higher resistance following mild oxidative stress treatments when compared to control cells. Furthermore, the expression of NS in a pro-apoptotic mutant strain-induced cell death during aging. Overall, these data recapitulate phenotypes observed in mammalian cells, thereby validating as a model for FENIB.
家族性神经丝氨酸蛋白酶包涵体脑病（FENIB）是一种由该基因点突变引起的人类单基因疾病，其特征是神经丝氨酸蛋白酶（NS）聚合物在细胞内沉积，导致蛋白毒性和细胞死亡。尽管迄今为止已经开发了不同的细胞和动物模型，但NS聚合物引发细胞毒性的确切机制仍不清楚。在这里，我们报告说，人类野生型NS和聚合变体G392E NS在酵母中表达时形成主要定位于内质网（ER）内的蛋白质聚集体。NS在酵母中的表达延迟了从延迟期的退出，表明NS包涵体引起细胞应激。与对照细胞相比，这些细胞在轻度氧化应激处理后也表现出更高的抗性。此外，NS在促凋亡突变株中的表达在衰老过程中诱导细胞死亡。总体而言，这些数据概括了在哺乳动物细胞中观察到的表型，从而验证了作为FENIB模型的有效性。
