Abstract

Glutathione S-transferase omega (GSTO) is an antioxidant enzyme involved in reducing oxidative stress. Recent studies suggest that polymorphic variants of GSTOs affect the onset age and progression of neurodegenerative diseases. Although GSTO activity may affect the development and age dependency of several diseases, the mechanism by which GSTO inactivation in neurons regulates the susceptibility to neurodegenerative diseases is unclear. In the present study, GstO2 knockdown in Drosophila led to increased levels of Cabeza (Caz) protein in neurons in an age-dependent manner. Drosophila Caz is the ortholog of human FUS, which is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that cytoplasmic Caz mislocalization and aggregation in neurons significantly increased after GstO2 knockdown in vivo. Downregulation of GstO2 decreased the solubility of the Caz protein in aging neurons. These findings demonstrate that GSTO is a critical modulator of the development of neurodegenerative diseases by regulating Caz localization and aggregation in the nervous system of Drosophila.

摘要

谷胱甘肽 S-转移酶 omega (GSTO) 是一种抗氧化酶，参与减少氧化应激。最近的研究表明，GSTO 的多态性变异会影响神经退行性疾病的发病年龄和进展。尽管 GSTO 活性可能影响多种疾病的发生和年龄依赖性，但神经元中 GSTO 失活调节神经退行性疾病易感性的机制尚不清楚。在本研究中，果蝇中的GstO2敲低导致神经元中 Cabeza (Caz) 蛋白水平以年龄依赖性方式增加。果蝇Caz 是人类 FUS 的直系同源物，FUS 与神经退行性疾病有关，包括肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD)。我们发现体内GstO2敲低后，神经元细胞质 Caz 的错误定位和聚集显着增加。GstO2的下调降低了衰老神经元中 Caz 蛋白的溶解度。这些发现表明，GSTO 通过调节果蝇神经系统中 Caz 的定位和聚集，成为神经退行性疾病发展的关键调节剂。