Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile; Santiago, Chile.
Autophagy. 2013 Sep;9(9):1308-20. doi: 10.4161/auto.25188. Epub 2013 Jun 6.
Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, is a pathological hallmark of ALS. Autophagy is the major degradation pathway involved in the clearance of damaged organelles and protein aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant protein in cell culture models, several studies suggest that autophagy impairment may also contribute to disease pathogenesis. In this report, we tested the potential use of trehalose, a disaccharide that induces MTOR-independent autophagy, in the development of experimental ALS. Administration of trehalose to mutant SOD1 transgenic mice significantly prolonged life span and attenuated the progression of disease signs. These effects were associated with decreased accumulation of SOD1 aggregates and enhanced motoneuron survival. The protective effects of trehalose were associated with increased autophagy levels in motoneurons. Cell culture experiments demonstrated that trehalose led to mutant SOD1 degradation by autophagy in NSC34 motoneuron cells and also protected primary motoneurons against the toxicity of conditioned media from mutant SOD1 transgenic astrocytes. At the mechanistic level, trehalose treatment led to a significant upregulation in the expression of key autophagy-related genes at the mRNA level including Lc3, Becn1, Sqstm1 and Atg5. Consistent with these changes, trehalose administration enhanced the nuclear translocation of FOXO1, an important transcription factor involved in the activation of autophagy in neurons. This study suggests a potential use of trehalose and enhancers of MTOR-independent autophagy for the treatment of ALS.
肌萎缩侧索硬化症（ALS）是一种致命的运动神经元疾病，目前尚无有效的治疗方法。异常蛋白聚集体的积累，包含 SOD1、TARDBP、FUS 等蛋白，是 ALS 的病理标志之一。自噬是参与清除受损细胞器和蛋白聚集体的主要降解途径。尽管自噬已被证明能在细胞培养模型中有效降解 ALS 相关的突变蛋白，但几项研究表明，自噬功能障碍也可能导致疾病的发生。在本报告中，我们测试了海藻糖（一种诱导 MTOR 非依赖性自噬的二糖）在实验性 ALS 中的潜在用途。海藻糖对突变 SOD1 转基因小鼠的给药显著延长了生存期并减缓了疾病症状的进展。这些效果与 SOD1 聚集体积累的减少和运动神经元存活的增加有关。海藻糖的保护作用与运动神经元中自噬水平的增加有关。细胞培养实验表明，海藻糖通过 NSC34 运动神经元细胞中的自噬导致突变 SOD1 降解，并且还能防止来自突变 SOD1 转基因星形胶质细胞的条件培养基对原代运动神经元的毒性。在机制水平上，海藻糖处理导致关键自噬相关基因的表达在 mRNA 水平上显著上调，包括 Lc3、Becn1、Sqstm1 和 Atg5。与这些变化一致，海藻糖给药增强了 FOXO1 的核易位，FOXO1 是神经元中自噬激活的重要转录因子。这项研究表明海藻糖和 MTOR 非依赖性自噬增强剂在 ALS 治疗中的潜在用途。
