Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.
Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.
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不间断的CAG重复驱动纹状体选择性转录病和人类亨廷顿蛋白BAC小鼠的核发病机理。
DOI：
10.1016/j.neuron.2022.01.006
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发表时间：
2022-04-06
期刊：
影响因子：
16.2
通讯作者：
Yang, X. William
中科院分区：
文献类型：
--
作者：
Gu, Xiaofeng;Richman, Jeffrey;Langfelder, Peter;Wang, Nan;Zhang, Shasha;Banez-Coronel, Monica;Wang, Huei-Bin;Yang, Lucia;Ramanathan, Lalini;Deng, Linna;Park, Chang Sin;Choi, Christopher R.;Cantle, Jeffrey P.;Gao, Fuying;Gray, Michelle;Coppola, Giovanni;Bates, Gillian P.;Ranum, Laura P. W.;Horvath, Steve;Colwell, Christopher S.;Yang, X. William
在亨廷顿病(HD)中，不间断的CAG重复长度，而不是聚谷氨酰胺长度，可以预测疾病的发生。然而，潜在的病理生物学仍不清楚。在这里，我们开发了细菌人工染色体(BAC)转基因小鼠，表达人类突变亨廷顿蛋白(MHTT)，具有不间断的、身体不稳定的CAG重复序列，表现出与疾病相关的进行性表型。与之前具有稳定的、CAA中断的、多谷氨酰胺编码重复序列的mHTT转基因模型不同，BAC-CAG小鼠显示出强大的纹状体选择性核包涵体和转录失调，类似于小鼠亨廷顿蛋白敲打模型和HD患者。重要的是，HD模型的纹状体转录异常与其不间断的CAG重复长度显著相关，而与多谷氨酰胺长度无关。最后，在起源于mHTT基因组转基因且仅存在或丰富于不间断CAG重复模型的致病实体中，体细胞CAG重复不稳定和核mHTT聚集与早期纹状体选择性分子发病以及运动和睡眠障碍相关性最好，而重复RNA相关病理学和重复相关非AUG(RAN)翻译可能分别起到较小的选择性或晚期致病作用。使用一种新的人类基因组BAC转基因HD小鼠模型，具有长的不间断CAG重复，Gu等人。提供了分子、病理学和行为学数据，证明了突变的HTT中不间断的CAG重复在体内诱发纹状体选择性致病中的关键致病作用，而不是其编码的聚谷氨酰胺蛋白。
In Huntington’s disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively. Using a novel human genomic BAC transgenic mouse model of HD with long uninterrupted CAG repeats, Gu et al. provided molecular, pathological, and behavioral data to demonstrate critical pathogenic roles of uninterrupted CAG repeats in mutant HTT, beyond its encoded polyglutamine protein, in eliciting striatum-selective pathogenesis in vivo.
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DOI：
10.1177/1073858410390378
发表时间：
2011-10
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Ehrnhoefer DE;Sutton L;Hayden MR
通讯作者：
Hayden MR
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：
3.7
作者：
Carty, Nikisha;Berson, Nadege;Kwak, Seung
通讯作者：
Kwak, Seung
影响因子：
11.1
作者：
Ciosi, Marc;Maxwell, Alastair;Monckton, Darren G.
通讯作者：
Monckton, Darren G.
DOI：
10.3233/jhd-210485
发表时间：
2021
期刊：
Journal of Huntington's disease
影响因子：
--
作者：
Hong EP;Chao MJ;Massey T;McAllister B;Lobanov S;Jones L;Holmans P;Kwak S;Orth M;Ciosi M;Monckton DG;Long JD;Lucente D;Wheeler VC;MacDonald ME;Gusella JF;Lee JM
通讯作者：
Lee JM