C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity.
C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity.
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DOI：
10.1093/hmg/ddx350
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发表时间：
2017-12-15
影响因子：
3.5
通讯作者：
Shaw CE
中科院分区：
文献类型：
--
作者：
Lee YB;Baskaran P;Gomez-Deza J;Chen HJ;Nishimura AL;Smith BN;Troakes C;Adachi Y;Stepto A;Petrucelli L;Gallo JM;Hirth F;Rogelj B;Guthrie S;Shaw CE
内含子GGGGCC （G4C2）六核苷酸重复扩增inC9orf72是肌萎缩性侧索硬化症和额颞叶痴呆（C9ALS/FTD）最常见的遗传原因。重复相关的非aug （RAN）翻译G4C2 RNA可导致五种不同的二肽重复蛋白（DPR：聚GA、聚GP、聚GR、聚PA和聚PR）聚集在受影响患者的神经元细胞质和核包涵体中，但它们在疾病发病机制中的作用仍存在争议。我们发现，在DPR蛋白中，poly GA在细胞培养模型中的表达以剂量依赖的方式激活程序性细胞死亡和TDP-43切割。poly GA与其他DPRs的双表达表明，poly GP和poly PA被poly GA隔离，而poly GR和poly PR很少与poly GA共定位。在鸡胚脊髓中，聚GA和聚PA的双表达通过抑制聚GA在体外和体内的聚集来改善聚GA的毒性。不同密码子衍生的ddprs在鸡胚胎脊髓中的表达证实了体外数据，表明每种二肽都有毒性，以聚GA毒性最大。此外，体内表达不同长度的G4C2重复序列导致凋亡细胞死亡，但不能产生DPRs。综上所述，这些数据表明c9相关的毒性可以由RNA或DPRs介导。此外，我们的研究结果提供了证据，证明聚GA是细胞毒性的关键介质，DPR蛋白之间的串扰可能改变了它们在C9ALS/FTD中的致病状态。
An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culture model activates programmed cell death and TDP-43 cleavage in a dose-dependent manner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being the most toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD.
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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：
16.2
作者：
Todd PK;Oh SY;Krans A;He F;Sellier C;Frazer M;Renoux AJ;Chen KC;Scaglione KM;Basrur V;Elenitoba-Johnson K;Vonsattel JP;Louis ED;Sutton MA;Taylor JP;Mills RE;Charlet-Berguerand N;Paulson HL
通讯作者：
Paulson HL
影响因子：
7.1
作者：
Sullivan PM;Zhou X;Robins AM;Paushter DH;Kim D;Smolka MB;Hu F
通讯作者：
Hu F
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：
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