Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway.
Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway.
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DOI：
10.1038/s41593-021-00859-9
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发表时间：
2021-08
影响因子：
25
通讯作者：
Bosco DA
中科院分区：
文献类型：
--
作者：
Lin YC;Kumar MS;Ramesh N;Anderson EN;Nguyen AT;Kim B;Cheung S;McDonough JA;Skarnes WC;Lopez-Gonzalez R;Landers JE;Fawzi NL;Mackenzie IRA;Lee EB;Nickerson JA;Grunwald D;Pandey UB;Bosco DA
随着年龄的增长和神经的退变，核细胞质转运(NCT)功能下降。在这里，我们研究了ALS融合肉瘤(FUS)模型中的NCT通路。ALS-FUS的表达导致NCT和核孔蛋白(Nup)在人神经元核膜内的密度降低。FUS和NUPS被发现在细胞内独立于RNA相互作用，并在体外改变彼此的相分离性质。FUS-Nup相互作用并不局限于核孔，而是在对照神经元的胞核中相对突变神经元的细胞质中丰富。我们的数据表明，ALS连锁突变对FUS的细胞质错误定位的影响，而不是对蛋白质本身的物理化学性质的影响，这是我们报道的NCT缺陷的基础。在果蝇的研究中，突变体FUS和NUPS之间的异常相互作用得到了强调，其中Nup表达的减少挽救了FUS诱导的多种毒性表型，包括神经元中异常的核膜形态。
Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of ALS-fused in sarcoma (FUS). Expression of ALS-FUS lead 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 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, where reduced Nup expression rescued multiple toxic FUS-induced phenotypes, including abnormal nuclear membrane morphology in neurons.
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影响因子：
15.1
作者：
Baron DM;Kaushansky LJ;Ward CL;Sama RR;Chian RJ;Boggio KJ;Quaresma AJ;Nickerson JA;Bosco DA
通讯作者：
Bosco DA
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：
16.6
作者：
Casci, Ian;Krishnamurthy, Karthik;Pandey, Udai Bhan
通讯作者：
Pandey, Udai Bhan
影响因子：
56.9
作者：
Frey, Steffen;Richter, Ralf P.;Goerlich, Dirk
通讯作者：
Goerlich, Dirk
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