Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.
Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.
复制标题
DOI：
10.1186/s40478-023-01665-z
复制
发表时间：
2023-10-17
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
确定家族性肌萎缩侧索硬化症（ALS）的遗传修饰基因可能揭示治疗调制的目标与散发性ALS的潜在应用。C9 orf 72基因中的GGGGCC（G4 C2）重复扩增是家族性ALS最常见形式的基础，并产生有毒的含精氨酸的二肽重复序列（DPR），其干扰无膜细胞器，如核仁。在这里，我们认为senataxin（SETX），ALS 4的遗传原因，作为C9 orf 72 ALS的修饰剂，因为SETX是一种核解旋酶，可以调节ALS功能障碍中涉及的RNA-蛋白质相互作用。在证明降低的SETX表达增强了HEK 293细胞和原代神经元中含精氨酸的DPR毒性和C9 orf 72重复扩增毒性后，我们产生了SETX果蝇系，并评估了SETX在表达（G4 C2）58重复或甘氨酸-精氨酸-50 [GR（50）] DPR的果蝇中的作用。我们在（G4 C2）58和GR（50）果蝇模型中观察到疾病表型的显著抑制，并在共表达SETX的果蝇中检测到GR（50）在核仁外的显著重新定位。下一代GR（1000）果蝇模型在攀爬和运动测定中显示出年龄相关的运动缺陷，用SETX共表达类似地挽救。我们注意到，SETX和含精氨酸的DPRs之间的物理相互作用部分依赖于RNA。最后，我们直接评估了表达GR-DPR的细胞中的核仁，证实了在GR-DPR表达后运输到核仁的蛋白质的流动性降低，并且发现SETX剂量调节了表达GR-DPR的细胞和运动神经元中的核仁流动性。这些发现揭示了SETX功能和细胞过程之间迄今未知的联系，这些细胞过程在最常见的家族性ALS中导致神经元死亡。在线版本包含补充材料，可通过10.1186/s40478-023-01665-z获得。
Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA–protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS. The online version contains supplementary material available at 10.1186/s40478-023-01665-z.
登录
查看更多内容
影响因子：
17.1
作者：
Burberry A;Suzuki N;Wang JY;Moccia R;Mordes DA;Stewart MH;Suzuki-Uematsu S;Ghosh S;Singh A;Merkle FT;Koszka K;Li QZ;Zon L;Rossi DJ;Trowbridge JJ;Notarangelo LD;Eggan K
通讯作者：
Eggan K
DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
16
作者：
Marmor-Kollet H;Siany A;Kedersha N;Knafo N;Rivkin N;Danino YM;Moens TG;Olender T;Sheban D;Cohen N;Dadosh T;Addadi Y;Ravid R;Eitan C;Toth Cohen B;Hofmann S;Riggs CL;Advani VM;Higginbottom A;Cooper-Knock J;Hanna JH;Merbl Y;Van Den Bosch L;Anderson P;Ivanov P;Geiger T;Hornstein E
通讯作者：
Hornstein E
影响因子：
6.1
作者：
Chen, Ying-Zhang;Hashemi, Sayed H.;Bennett, Craig L.
通讯作者：
Bennett, Craig L.