Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Neurology, Hebei General Hospital, Shijiazhuang, China.
FEBS J. 2024 Feb;291(4):795-813. doi: 10.1111/febs.17009. Epub 2023 Dec 1.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.
肌萎缩侧索硬化症（ALS）是一种以进行性运动神经元（MN）死亡为特征的神经退行性疾病。超氧化物歧化酶 1（SOD1）基因突变，导致异常蛋白聚集，是家族性 ALS 的原因之一。SOD1-G93A 突变小鼠在疾病进展过程中会出现自噬功能障碍，但该病的病因仍不清楚。optineurin（OPTN）是一种参与自噬的衔接蛋白，参与聚噬体和线粒体自噬。先前的研究已经确定 OPTN 突变导致青光眼和 ALS 等疾病。然而，OPTN 在 ALS 模型中的自噬和线粒体自噬功能尚未得到深入研究。在这项研究中，我们通过鞘内注射腺相关病毒 9（AAV9）-OPTN 到 SOD1-G93A 转基因小鼠和转染表达 SOD1-G93A 突变蛋白的细胞来评估 OPTN 对自噬和线粒体功能的有益影响。OPTN 基因治疗后电压依赖性阴离子通道 1（VDAC1）表达增加，自噬水平升高，p62 水平降低，微管相关蛋白 1A/1B-轻链 3（LC3）-II 水平升高。此外，通过电子显微镜观察到线粒体跨膜电位超极化和线粒体形态异常的逆转。此外，TANK 结合激酶 1（TBK1）的蛋白水平升高，表明线粒体自噬增加。我们在动物和细胞系研究中的发现强烈表明，OPTN 基因治疗是一种增加自噬和保护线粒体以防止 ALS 进展的有效策略，并且可能对 ALS 的治疗有效。
