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IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons.
EMBO Reports ( IF 6.5 ) Pub Date : 2020-02-07 , DOI: 10.15252/embr.201949129
Alexander D Fellows 1 , Elena R Rhymes 1 , Katherine L Gibbs 1 , Linda Greensmith 1 , Giampietro Schiavo 1, 2, 3
Affiliation  

Signalling endosomes are essential for trafficking of activated ligand-receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, we describe a new modulator of signalling endosome trafficking, the insulin-like growth factor 1 receptor (IGF1R). We show that IGF1R inhibition increases the velocity of signalling endosomes in motor neuron axons, both in vitro and in vivo. This effect is specific, since IGF1R inhibition does not alter the axonal transport of mitochondria or lysosomes. Our results suggest that this change in trafficking is linked to the dynein adaptor bicaudal D1 (BICD1), as IGF1R inhibition results in an increase in the de novo synthesis of BICD1 in the axon of motor neurons. Finally, we found that IGF1R inhibition can improve the deficits in signalling endosome transport observed in a mouse model of amyotrophic lateral sclerosis (ALS). Taken together, these findings suggest that IGF1R inhibition may be a new therapeutic target for ALS.

中文翻译:

IGF1R调节运动神经元中信号内体的逆行轴突运输。

信号传递内体对于活化的配体-受体复合物的运输及其远端信号传递至关重要,最终导致神经元存活。尽管信号传递内体运输的缺陷已与神经退行性疾病有关,但我们对控制该过程的机制的理解仍不完全。在这里,我们描述了一种信号传导内体运输的新型调节剂,胰岛素样生长因子1受体(IGF1R)。我们显示,IGF1R抑制作用可增加体内和体外运动神经元轴突中信号传递内体的速度。由于IGF1R的抑制作用不会改变线粒体或溶酶体的轴突转运,因此这种作用是特异性的。我们的结果表明,贩运活动的这种变化与动力蛋白适配器比克拉多尔D1(BICD1)相关,因为IGF1R抑制作用导致运动神经元轴突中BICD1的从头合成增加。最后,我们发现IGF1R抑制作用可以改善肌萎缩性侧索硬化症(ALS)小鼠模型中观察到的内体转运信号的缺陷。综上,这些发现表明,IGF1R抑制可能是ALS的新治疗靶标。
更新日期:2020-03-04
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