Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models.
Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models.
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DOI：
10.1093/hmg/ddz230
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发表时间：
2019-10
影响因子：
3.5
通讯作者：
Chen Liang;Q. Shao;W. Zhang;Mei Yang;Qing-yun Chang;Rong Chen;Jian-Fu Chen
中科院分区：
文献类型：
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作者：
Chen Liang;Q. Shao;W. Zhang;Mei Yang;Qing-yun Chang;Rong Chen;Jian-Fu Chen
C9ORF72内含子中的G4C2重复扩增导致最常见的家族性肌萎缩性侧索硬化症和额颞叶痴呆（统称为C9ALS/FTD）。C9ALS/FTD发病机制和介导因子尚不清楚。C9orf72和Smcr8形成一种蛋白质复合物。在这里，我们发现Smcr8的表达与C9orf72一样，在C9ALS/FTD小鼠模型和患者组织中降低。由于Smcr8在人和小鼠之间高度保守，我们评估了Smcr8下调对小鼠的影响。Smcr8基因敲除（KO）小鼠表现出与C9ALS/FTD小鼠模型相似的运动行为缺陷，脊髓和神经肌肉连接处表现出轴突肿胀。这些缺陷是由突变的运动神经元轴突运输中断导致的自噬-溶酶体功能受损引起的。与Smcr8与C9orf72的相互作用及其在患者组织中的下调一致，Smcr8缺乏加剧了C9orf72 KO小鼠的自噬溶酶体损伤。在C9ALS/FTD小鼠模型中，Smcr8单倍体不足引起的轴突肿胀加重和毒性病理增加反映了Smcr8下调的疾病相关性。因此，我们的体内研究表明，在C9ALS/FTD小鼠模型中，Smcr8缺乏会损害轴突转运依赖的自噬溶酶体功能，并加剧轴突变性和毒性增加。
G4C2 repeat expansions in an intron of C9ORF72 cause the most common familial amyotrophic lateral sclerosis and frontotemporal dementia (collectively, C9ALS/FTD). Mechanisms and mediators of C9ALS/FTD pathogenesis remain poorly understood. C9orf72 and Smcr8 form a protein complex. Here we show that expression of Smcr8, like C9orf72, is reduced in C9ALS/FTD mouse models and patient tissues. Since Smcr8 is highly conserved between human and mouse, we evaluated the effects of Smcr8 downregulation in mice. Smcr8 knockout (KO) mice exhibited motor behavior deficits which resemble those of C9ALS/FTD mouse models, and displayed axonal swellings in their spinal cords and neuromuscular junctions. These deficits are caused by impaired autophagy-lysosomal functions due to disrupted axonal transport in mutant motor neurons. Consistent with its interaction with C9orf72 and their downregulation in patient tissues, Smcr8 deficiency exacerbated autophagy-lysosomal impairment in C9orf72 KO mice. The disease relevance of Smcr8 downregulation was reflected by exacerbated axonal swellings and gain of toxicity pathology arising from Smcr8 haploinsufficiency in a mouse model of C9ALS/FTD. Thus, our in vivo studies suggested that Smcr8 deficiency impairs axonal transport dependent autophagy-lysosomal function and exacerbates axonal degeneration and gain of toxicity in C9ALS/FTD mouse models.