Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.
Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS.
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DOI：
10.1126/scitranslmed.abe1923
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发表时间：
2021-07-28
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
核孔复合体(NPC)的组成和功能的改变被认为是包括C9orf72肌萎缩侧索硬化症/额颞叶痴呆(ALS/FTD)在内的遗传性神经退行性变的致病因素。我们推测，在ALS、FTD和相关神经退行性疾病中广泛观察到的TDP-43功能障碍和定位错误的上游可能存在Nup改变和相应的NPC功能丧失。在这里，我们提供了证据，在Nup改变出现之前，作为NPC质量控制的关键介质，CHMP7在C9orf72和散发性ALS诱导的多能干细胞(IPSC)来源的脊髓神经元(IPSN)和死后人类运动皮质的核中增加。抑制CHMP7的核输出导致Nup减少，TDP-43功能障碍和人神经元病理改变。CHMP7基因敲除可减轻疾病相关的Nup改变、RAN GTP酶定位缺陷、TDP-43相关mRNA表达缺陷以及下游谷氨酸诱导的神经元死亡。因此，我们的数据支持CHMP7介导的Nup稳态改变是家族性和散发性ALS的重要启动病理机制，并强调了CHMP7作为治疗靶点的潜力。
Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced pluripotent stem cell (iPSC)–derived spinal neurons (iPSNs) and postmortem human motor cortex before the emergence of Nup alterations. Inhibiting the nuclear export of CHMP7 triggered Nup reduction and TDP-43 dysfunction and pathology in human neurons. Knockdown of CHMP7 alleviated disease-associated Nup alterations, deficits in Ran GTPase localization, defects in TDP-43-associated mRNA expression, and downstream glutamate-induced neuronal death. Thus, our data support a role for altered CHMP7-mediated Nup homeostasis as a prominent initiating pathological mechanism for familial and sporadic ALS and highlight the potential for CHMP7 as therapeutic target.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
影响因子：
16.2
作者：
Kim HJ;Taylor JP
通讯作者：
Taylor JP
影响因子：
12.7
作者：
Johnson VE;Stewart W;Trojanowski JQ;Smith DH
通讯作者：
Smith DH
影响因子：
16.2
作者：
Coyne AN;Zaepfel BL;Hayes L;Fitchman B;Salzberg Y;Luo EC;Bowen K;Trost H;Aigner S;Rigo F;Yeo GW;Harel A;Svendsen CN;Sareen D;Rothstein JD
通讯作者：
Rothstein JD
影响因子：
15.1
作者：
Chew, Jeannie;Cook, Casey;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard