NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.
NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.
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DOI：
10.1038/s41467-022-31098-6
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发表时间：
2022-06-13
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
C9orf72基因中G4C2六核苷酸重复扩增是ALS和FTLD最常见的遗传原因（C9-ALS/FTLD），在神经退行性变区域观察到细胞质TDP-43内含物。重复rna的积累和二肽重复蛋白（DPR）是C9-ALS/FTLD毒性的两种被提出的机制，并与核胞质运输受损有关。核胞质运输是由苯丙氨酸-甘氨酸核孔蛋白（FG - nups）调节的，它构成核孔复合物（NPC）的渗透性屏障。然而，FG - up与TDP-43病理之间的关系尚不清楚。我们的研究表明，在C9-ALS/FTLD iPSC神经元中，一个FG nup （NUP62）的核缺失和细胞质错定位与TDP-43错定位有关。聚甘氨酸精氨酸（GR） DPR积累启动细胞质RNA颗粒的形成，募集NUP62和TDP-43。细胞质NUP62和TDP-43的相互作用促进了它们的不溶性，NUP62:TDP-43内含物经常在C9orf72 ALS/FTLD以及散发性ALS/FTLD死后中枢神经系统组织中发现。我们的研究结果表明，NUP62细胞质错误定位有助于ALS/FTLD的TDP-43蛋白病变。ALS和FTLD均以TDP43的不溶性细胞质沉积为特征。作者发现核孔蛋白NUP62在C9orf72和散发性ALS/FTLD中错定位，并提出它与TDP-43相互作用以促进其不溶性。
A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD. ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
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通讯作者：
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影响因子：
25
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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：
12.7
作者：
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通讯作者：
Shaw, Christopher E.