Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis
Motor Neuron-specific Disruption of Proteasomes, but Not Autophagy, Replicates Amyotrophic Lateral Sclerosis
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DOI：
10.1074/jbc.m112.417600
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发表时间：
2012-12-14
影响因子：
4.8
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
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作者：
Tashiro, Yoshitaka;Urushitani, Makoto;Takahashi, Ryosuke
有证据表明，蛋白质错误折叠在肌萎缩侧索硬化症(ALS)的发病机制中起关键作用。然而，由于先前相互矛盾的结果，关于蛋白酶体或自噬在ALS中的参与仍然存在争议。在这里，我们证明了运动神经元中泛素-蛋白酶体系统的损伤，而不是自噬-溶酶体系统的损伤会在小鼠中复制ALS。运动神经元特异性的蛋白酶体亚基Rpt3条件性敲除小鼠(Rpt3-CKO)表现出运动功能障碍，并伴有进行性运动神经元丢失和胶质细胞增生。此外，不同的ALS相关蛋白，包括TAR DNA结合蛋白43 kDa(TDP-43)、肉瘤融合蛋白(FUS)、泛素2和视神经磷酸酶在运动神经元中错误定位或聚集，以及其他典型的ALS特征，如嗜碱性包涵体。另一方面，运动神经元特异性敲除的ATG7是诱导自噬的关键成分(ATG7-CKO)，仅导致泛素和p62的胞浆积聚，没有观察到TDP-43或FUS病理或运动功能障碍。这些结果强烈表明，蛋白酶体，而不是自噬，从根本上控制着ALS的发展，TDP-43和FUS蛋白病可能在其中发挥关键作用。增强蛋白酶体活性可能是治疗ALS的一种有前途的策略。
Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS-linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS.