Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD.
Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD.
复制标题
DOI：
10.1016/j.celrep.2022.111379
复制
发表时间：
2022-09-20
期刊：
影响因子：
8.8
通讯作者：
Lloyd, Thomas E.
中科院分区：
文献类型：
--
作者：
Dubey, Sandeep Kumar;Maulding, Kirstin;Sung, Hyun;Lloyd, Thomas E.
核孔复合体（NPC）和核质转运（NCT）的破坏与神经退行性疾病的发病机制有关。C9 orf 72基因内含子中的GGGGCC六核苷酸重复扩增（HRE）是肌萎缩侧索硬化症和额颞叶痴呆的最常见遗传原因，但HRE破坏NCT的机制尚不完全清楚。我们发现，在果蝇神经元中的GGGGCC重复序列的表达诱导蛋白酶体介导的选择NPC的核孔蛋白的降解。这个过程需要Vps 4 ATP酶和转运复合物-III（ESCRT-III）所需的内体分选复合物，因为ESCRT-III/Vps 4基因的敲低可以挽救核孔蛋白水平，使NCT正常化，并抑制GGGGCC介导的神经变性。GGGGCC表达上调核ESCRT-III/Vps 4表达，扩增显微镜显示核孔蛋白在经历蛋白酶体介导的降解之前易位到细胞质中。这些发现表明了神经退行性疾病中核孔蛋白降解和NPC功能障碍的机制。Dubey et al.表明，在C9-ALS/FTD果蝇模型中，神经元中ESCRT-III/Vps 4复合物的核水平升高导致通过蛋白酶体途径构成核孔复合物的核孔蛋白降解。ESCRT-III/Vps 4复合蛋白的敲低恢复核孔蛋白水平和核质转运并抑制神经变性。
Disruption of the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been implicated in the pathogenesis of neurodegenerative diseases. A GGGGCC hexanucleotide repeat expansion (HRE) in an intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, but the mechanism by which the HRE disrupts NCT is incompletely understood. We find that expression of GGGGCC repeats in Drosophila neurons induces proteasome-mediated degradation of select nucleoporins of the NPC. This process requires the Vps4 ATPase and the endosomal-sorting complex required for transport complex-III (ESCRT-III), as knockdown of ESCRT-III/Vps4 genes rescues nucleoporin levels, normalizes NCT, and suppresses GGGGCC-mediated neurodegeneration. GGGGCC expression upregulates nuclear ESCRT-III/Vps4 expression, and expansion microscopy demonstrates that the nucleoporins are translocated into the cytoplasm before undergoing proteasome-mediated degradation. These findings demonstrate a mechanism for nucleoporin degradation and NPC dysfunction in neurodegenerative disease. Dubey et al. show that increased nuclear levels of the ESCRT-III/Vps4 complex in neurons causes degradation of nucleoporins that make up the nuclear pore complex through the proteasome pathway in fly models of C9-ALS/FTD. Knockdown of ESCRT-III/Vps4 complex proteins restores nucleoporin levels and nucleocytoplasmic transport and suppresses neurodegeneration.
登录
查看更多内容
光学成像。膨胀显微镜。
DOI：
10.1126/science.1260088
发表时间：
2015-01-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen F;Tillberg PW;Boyden ES
通讯作者：
Boyden ES
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：
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：
12.7
作者：
Cooper-Knock J;Higginbottom A;Stopford MJ;Highley JR;Ince PG;Wharton SB;Pickering-Brown S;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
17.1
作者：
通讯作者：
--