Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.
Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.
复制标题
DOI：
10.1159/000437208
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Yao TP
中科院分区：
文献类型：
--
作者：
Lee JY;Kawaguchi Y;Li M;Kapur M;Choi SJ;Kim HJ;Park SY;Zhu H;Yao TP
蛋白质聚集体的异常积累是许多神经退行性疾病的病理标志，包括肌萎缩侧索硬化症（ALS）。尽管蛋白质聚集体的积累经常导致细胞死亡，但它是否是驱动神经退行性疾病的关键致病因素仍然存在争议。 HDAC6 是一种胞质泛素结合脱乙酰酶，已成为泛素依赖性 QC 自噬的重要调节因子，QC 自噬是一种溶酶体依赖性降解系统，负责处理错误折叠的蛋白质聚集体和受损的细胞器。在这里，我们表明，在细胞模型中，HDAC6 通过促进多种与疾病相关且易于聚集的胞质蛋白降解，从而发挥保护作用。我们进一步表明，HDAC6 是溶酶体有效定位到蛋白质聚集体所必需的，这表明溶酶体对自噬底物的靶向受到调节。在转基因 SOD1G93A 小鼠（ALS 模型）中对 HDAC6 进行基因消除，可支持 HDAC6 在体内蛋白质聚集体处理中发挥关键作用，从而导致泛素化 SOD1G93A 蛋白质聚集体的大量积累。令人惊讶的是，尽管 SOD1G93A 聚集体大量积累，但 HDAC6 的删除仅适度改变了运动表型。这些发现表明 SOD1G93A 聚集并不是驱动 ALS 神经变性的唯一决定因素，并且 HDAC6 可能通过蛋白质聚集物清除之外的其他机制调节神经变性。
Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent QC autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models, HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance.