Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion.
Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion.
复制标题
通过 C9ORF72 重复扩增，靶向 ALS 患者 iPSC 衍生运动神经元中的 RNA 焦点。
DOI：
10.1126/scitranslmed.3007529
复制
发表时间：
2013-10-23
影响因子：
17.1
通讯作者：
Baloh RH
中科院分区：
文献类型：
--
作者：
Sareen D;O'Rourke JG;Meera P;Muhammad AK;Grant S;Simpkinson M;Bell S;Carmona S;Ornelas L;Sahabian A;Gendron T;Petrucelli L;Baughn M;Ravits J;Harms MB;Rigo F;Bennett CF;Otis TS;Svendsen CN;Baloh RH
肌萎缩性侧索硬化症（ALS）是一种严重的神经退行性疾病，其特征是大脑和脊髓中运动神经元的丧失。C9ORF72基因非编码区六核苷酸重复序列（GGGGCC）的扩增是家族性ALS （C9-ALS）以及额颞叶变性和其他神经系统疾病的最常见原因。重复扩增如何导致疾病尚不清楚，功能丧失（单倍体功能不全）和功能获得（有毒RNA或蛋白质产物）都被提出。在这里，我们报道了一种C9-ALS细胞模型，其运动神经元是从来自ALS患者的诱导多能干细胞（iPSCs）中分化出来的，该细胞携带C9ORF72重复扩增。没有观察到C9ORF72表达的显著丧失，并且转录物的敲低对培养的人类运动神经元没有毒性。重复序列的转录增加，导致含有GGGGCC重复序列的RNA病灶选择性地在C9-ALS运动神经元中积累。含有重复序列的RNA与hnRNPA1和Pur-α共定位，表明它们可能能够改变RNA代谢。与对照运动神经元相比，C9-ALS运动神经元表现出与膜兴奋性相关的基因表达改变，包括DPP6，并且在去极化时表现出连续放电的能力减弱。针对C9ORF72转录物的反义寡核苷酸（ASOs）抑制了C9-ALS运动神经元中RNA病灶的形成并逆转了基因表达的改变。这些数据表明，患者来源的运动神经元可以用来描述ALS的致病事件。
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. Here, we report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS motor neurons. Repeat-containing RNA foci co-localized with hnRNPA1 and Pur-α, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides (ASOs) targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.
登录
查看更多内容
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：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
16.2
作者：
Kordasiewicz HB;Stanek LM;Wancewicz EV;Mazur C;McAlonis MM;Pytel KA;Artates JW;Weiss A;Cheng SH;Shihabuddin LS;Hung G;Bennett CF;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
4.4
作者：
Kim, Yong Man;Jang, Won Hee;Quezado, Martha M.;Oh, Yohan;Chung, Kwang Chul;Junn, Eunsung;Mouradian, M. Maral
通讯作者：
Mouradian, M. Maral
影响因子：
23.9
作者：
通讯作者：
--