小柯机器人

美国麻省大学医学院Daryl A. Bosco研究小组发现，ALS相关的FUS和核孔蛋白之间的相互作用与核质转运途径中的缺陷有关。2021年5月31日，国际知名学术期刊《自然—神经科学》在线发表了这一成果。

研究人员报道了肌萎缩侧索硬化（ALS-FUS）模型中的核细胞质转运（NCT）通路。ALS-FUS的表达导致人类神经元核膜内NCT和核孔蛋白（Nup）密度的降低。研究人员发现了FUS和Nup不依赖RNA的细胞内相互作用，并在体外改变彼此的相分离特性。FUS-Nup相互作用不局限于核孔，而是在对照神经元的细胞核与突变神经元的细胞质中富集。

数据表明，ALS相关突变对FUS细胞质错误定位的影响，而不是对蛋白质本身的理化特性的影响，这也是NCT缺陷的基础。果蝇研究强调了突变FUS和Nup之间的异常相互作用，因此减少Nup的表达挽救了多种有毒FUS诱导的表型，包括神经元中异常的核膜形态。

据悉，NCT下降会随着衰老和神经变性而发生。

附：英文原文

Title: Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway

Author: Yen-Chen Lin, Meenakshi Sundaram Kumar, Nandini Ramesh, Eric N. Anderson, Aivi T. Nguyen, Boram Kim, Simon Cheung, Justin A. McDonough, William C. Skarnes, Rodrigo Lopez-Gonzalez, John E. Landers, Nicolas L. Fawzi, Ian R. A. Mackenzie, Edward B. Lee, Jeffrey A. Nickerson, David Grunwald, Udai B. Pandey, Daryl A. Bosco

Issue&Volume: 2021-05-31

Abstract: Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of amyotrophic lateral sclerosis–fused in sarcoma (ALS–FUS). Expression of ALS–FUS led to a reduction in NCT and nucleoporin (Nup) density within the nuclear membrane of human neurons. FUS and Nups were found to interact independently of RNA in cells and to alter the phase-separation properties of each other in vitro. FUS–Nup interactions were not localized to nuclear pores, but were enriched in the nucleus of control neurons versus the cytoplasm of mutant neurons. Our data indicate that the effect of ALS-linked mutations on the cytoplasmic mislocalization of FUS, rather than on the physiochemical properties of the protein itself, underlie our reported NCT defects. An aberrant interaction between mutant FUS and Nups is underscored by studies in Drosophila, whereby reduced Nup expression rescued multiple toxic FUS-induced phenotypes, including abnormal nuclear membrane morphology in neurons.

DOI: 10.1038/s41593-021-00859-9

Source: https://www.nature.com/articles/s41593-021-00859-9

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex