HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.
HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.
复制标题
HNRNPK 通过抵消 C9orf72 ALS 中的 DNA 损伤来减轻 RNA 毒性。
DOI：
10.1007/s00401-022-02471-y
复制
发表时间：
2022-09
影响因子：
12.7
通讯作者：
中科院分区：
文献类型：
--
作者：
C9orf72基因第一个内含子中的“GGGGCC”重复扩增是肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。导致这些神经退行性疾病的确切机制尚不清楚，但C9重复RNA毒性已被认为是一种功能获得机制。我们的目的是使用斑马鱼C9orf72 RNA毒性模型来鉴定als相关表型的修饰因子。我们发现RNA结合蛋白异质核核糖核蛋白K （HNRNPK）可以逆转义和反义重复RNA的毒性，这取决于其亚细胞定位和RNA识别，而不是C9orf72重复RNA结合。我们在C9orf72 ALS患者成纤维细胞、诱导多能干细胞（iPSC）衍生的运动神经元、死后运动皮质和脊髓中观察到HNRNPK细胞质错定位，这与C9orf72 ALS患者HNRNPK功能紊乱一致。在C9orf72 ALS/FTD患者组织中，我们发现核易位增加，但核糖核苷酸还原酶调节亚基M2 （RRM2）的表达减少，RRM2是HNRNPK参与DNA损伤反应的下游靶标。最后，我们发现增加HNRNPK或RRM2的表达足以减轻C9orf72 RNA毒性斑马鱼模型中的DNA损伤。总的来说，我们的研究加强了RNA毒性作为C9orf72 ALS致病机制的相关性，并证明了其与异常DNA损伤反应的联系，为C9orf72 ALS/FTD开辟了新的治疗途径。在线版本包含补充材料，下载地址为10.1007/s00401-022-02471-y。
A ‘GGGGCC’ repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The exact mechanism resulting in these neurodegenerative diseases remains elusive, but C9 repeat RNA toxicity has been implicated as a gain-of-function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS-linked phenotype. We discovered that the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) reverses the toxicity of both sense and antisense repeat RNA, which is dependent on its subcellular localization and RNA recognition, and not on C9orf72 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts, induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem motor cortex and spinal cord, in line with a disrupted HNRNPK function in C9orf72 ALS. In C9orf72 ALS/FTD patient tissue, we discovered an increased nuclear translocation, but reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), a downstream target of HNRNPK involved in the DNA damage response. Last but not least, we showed that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9orf72 RNA toxicity zebrafish model. Overall, our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9orf72 ALS and demonstrates its link with an aberrant DNA damage response, opening novel therapeutic avenues for C9orf72 ALS/FTD. The online version contains supplementary material available at 10.1007/s00401-022-02471-y.
影响因子：
3.7
作者：
Wang, Yan;Musich, Phillip R.;Cui, Kui;Zou, Yue;Zhu, Meng-Yang
通讯作者：
Zhu, Meng-Yang