Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.
Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.
复制标题
DOI：
10.1038/s41467-021-27221-8
复制
发表时间：
2021-11-25
影响因子：
16.6
通讯作者：
Perlson E
中科院分区：
文献类型：
--
作者：
Altman T;Ionescu A;Ibraheem A;Priesmann D;Gradus-Pery T;Farberov L;Alexandra G;Shelestovich N;Dafinca R;Shomron N;Rage F;Talbot K;Ward ME;Dori A;Krüger M;Perlson E
主要是核RNA/DNA结合蛋白TDP-43的错误定位发生在约95%的肌萎缩侧索硬化症（ALS）患者的运动神经元中，但轴突TDP-43对这种神经退行性疾病的贡献尚不清楚。在这里，我们显示了TDP-43在来自ALS患者的肌内神经中和ALS患者的人iPSC衍生的运动神经元的轴突中以及TDP-43错误定位小鼠模型的运动神经元和神经肌肉接头（NMJ）中的积累。在轴突中，TDP-43被过度磷酸化并促进G3BP1阳性核糖核蛋白（RNP）缩合物组装，从而抑制远端轴突和NMJ中的局部蛋白质合成。具体而言，轴突和突触水平的核编码的线粒体蛋白减少。轴突TDP-43的清除或G3BP1缩合物的解离恢复了局部翻译，并解决了轴突和NMJ中TDP-43衍生的毒性。这些发现支持TDP-43在ALS中的功能的轴突增益，其可以被靶向用于治疗开发。在这里，作者在来自ALS患者的人iPSC衍生的运动神经元和TDP-43小鼠模型中显示，轴突TDP-43形成G3BP1阳性RNP缩合物，其隔离核编码的线粒体蛋白的mRNA并减少运动神经元轴突和神经肌肉接头中的局部蛋白质合成。
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development. Here, the authors show in human iPSC-derived motor neurons from ALS patients and a TDP-43 mouse model that axonal TDP-43 forms G3BP1 positive RNP condensates, which sequester mRNA of nuclear encoded mitochondrial proteins and decrease local protein synthesis in motor neuron axons and neuromuscular junctions.
登录
查看更多内容
影响因子：
3
作者：
Costa CJ;Willis DE
通讯作者：
Willis DE
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：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
16.2
作者：
Fang, Mark Y.;Markmiller, Sebastian;Yeo, Gene W.
通讯作者：
Yeo, Gene W.
影响因子：
4.8
作者：
Chen, Youjun;Cohen, Todd J.
通讯作者：
Cohen, Todd J.