A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.
A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.
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DOI：
10.1371/journal.pgen.1002481
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Martí E
中科院分区：
文献类型：
--
作者：
Bañez-Coronel M;Porta S;Kagerbauer B;Mateu-Huertas E;Pantano L;Ferrer I;Guzmán M;Estivill X;Martí E
亨廷顿病（HD）是一种由亨廷顿蛋白（HTT）基因CAG重复序列扩增引起的常染色体显性遗传疾病。由CAG重复序列编码的HTT蛋白中异常延伸的多聚谷氨酰胺具有毒性作用。在这里，我们提供的证据支持，突变HTT CAG重复干扰细胞活力在RNA水平。在人类神经元细胞中，CAG重复长度超过完全缺失阈值（40或更大）的扩增HTT外显子1 mRNA诱导细胞死亡，并以Dicer依赖性方式增加21个核苷酸的小CAG重复RNA（sCAG）水平。HTT mRNA和sCAG产生的毒性作用的严重程度与CAG扩增长度相关。从表达突变HTT的细胞和HD人脑中获得的小RNA以Ago 2依赖性机制显著降低神经元活力。在这两种情况下，使用对sCAG特异性的抗miR有效地阻断了毒性作用，支持了sCAG在HTT介导的毒性中的关键作用。荧光素酶报告基因分析表明，扩大HTT沉默的表达CTG含有基因下调HD。这些结果表明HD和sCAG表达与siRNA/miRNA基因沉默机制的异常激活之间可能存在联系，这可能引发有害反应。识别受sCAG影响的特定细胞过程可能会深入了解HD的致病机制，为开发新的治疗方法提供机会。亨廷顿病（HD）是由亨廷顿蛋白基因（HTT）中异常CAG扩增引起的神经退行性疾病，导致HTT蛋白中多聚谷氨酰胺轨道扩增。较长的CAG扩张与早期更严重的疾病表现相关，这些表现会产生舞蹈动作、行为和精神障碍以及痴呆。虽然致病基因广泛表达，但神经病理学的特征是纹状体和皮质萎缩。HTT与参与转录、细胞信号传导和转运的蛋白质相互作用。突变HTT的致病作用尚未完全了解。这项研究表明，CAG扩增的HTT RNA也有助于神经元毒性。突变HTT RNA产生具有神经毒性活性的小CAG重复RNA（sCAG）。这些短RNA通过与microRNA类似的机制，通过沉默完全或部分互补的基因的表达来干扰细胞功能。这些发现表明，一个小的RNA依赖性机制可能有助于HD神经元细胞的损失。对sCAG调控的靶基因的详尽鉴定可能会更好地理解HD病理学，从而开发新的治疗策略。
Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches. Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG expansion in the Huntingtin gene (HTT), resulting in an expanded polyglutamine track in the HTT protein. Longer CAG expansions correlate with an earlier more severe manifestation of the disease that produces choreic movement, behavioural and psychiatric disturbances, and dementia. Although the causative gene is widely expressed, neuropathology is characterized by striatal and cortical atrophy. HTT interacts with proteins involved in transcription, cell signaling, and transport. The pathogenic role of mutant HTT is not fully understood. This study shows that CAG expanded HTT RNA also contributes to neuronal toxicity. Mutant HTT RNA gives rise to small CAG-repeated RNAs (sCAGs) with neurotoxic activity. These short RNAs interfere with cell functions by silencing the expression of genes that are fully or partially complementary, through a mechanism similar to that of microRNAs. These findings suggest that a small RNA–dependent mechanism may contribute to HD neuronal cell loss. The exhaustive identification of the target genes modulated by sCAGs may lead to a better understanding of HD pathology, allowing the development of new therapeutic strategies.
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30.8
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ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
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