Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity.
Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity.
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DOI：
10.3389/fncel.2023.1134090
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发表时间：
2023
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
C9 orf 72基因中的内含子重复序列扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见的已知单一遗传原因。这些重复扩增被认为会导致功能丧失和毒性功能获得。功能获得导致产生有毒的富含精氨酸的二肽重复蛋白（DPR），即polyGR和polyPR。I型蛋白质精氨酸甲基转移酶（PRMT）的小分子抑制剂已被证明可以保护NSC-34细胞和原代小鼠源性脊髓神经元免受polyGR和polyPR攻击引起的毒性，但尚未探索其在人类运动神经元（MN）中的作用。为了研究这一点，我们产生了一组C9 orf 72纯合子和半合子敲除的iPSC，以检查C9 orf 72功能丧失对疾病发病机制的贡献。我们将这些iPSC分化为脊髓运动神经元（sMN）。我们发现C9 orf 72水平的降低以剂量依赖性方式加剧了polyGR 15的毒性。I型PRMT抑制能够部分挽救野生型和C9 orf 72扩增的sMN中的聚GR 15毒性。本研究探讨了C9 orf 72 ALS中功能丧失和功能获得毒性的相互作用。它还暗示I型PRMT抑制剂可能是polyGR毒性的调节剂。
Intronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored. To study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs). We found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs. This study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.
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影响因子：
5.4
作者：
Gendron, Tania F.;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard
影响因子：
4.6
作者：
Kanekura K;Harada Y;Fujimoto M;Yagi T;Hayamizu Y;Nagaoka K;Kuroda M
通讯作者：
Kuroda M
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：
5.1
作者：
Ikenaka, Kensuke;Maeda, Yasuhiro;Hotta, Yuji;Nagano, Seiichi;Yamada, Shinichiro;Ito, Daisuke;Torii, Ryota;Kakuda, Keita;Tatebe, Harutsugu;Atsuta, Naoki;Aguirre, Cesar;Kimura, Yasuyoshi;Baba, Kousuke;Tokuda, Takahiko;Katsuno, Masahisa;Kimura, Kazunori;Sobue, Gen;Mochizuki, Hideki
通讯作者：
Mochizuki, Hideki
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun