Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
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DOI：
10.1126/sciadv.adk1034
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发表时间：
2024-02-02
期刊：
影响因子：
13.6
通讯作者：
Chen, Jian-Fu
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Zhang, Minjie;Ma, Li;Jariyasakulroj, Supawadee;Chang, Qing;Lin, Ziying;Lu, Zhipeng;Chen, Jian-Fu
再现脑核糖体病的动物或人类模型是不完整的，阻碍了急需的治疗方法的开发。在这里，我们产生了遗传小鼠和人脑核糖体病的类器官模型，由小核仁RNA（snoRNA）SNORD 118突变引起。两种模型均表现出蛋白质合成损失、蛋白毒性应激和p53激活，并导致神经祖细胞（NPC）增殖减少和死亡增加，导致脑生长迟缓，重现人类患者的特征。SNORD 118功能的丧失导致整合应激反应（ISR）的介导因子p-eIF 2 α的异常上调。使用基于人类iPSC细胞的筛选，我们鉴定了小分子2BAct，一种ISR抑制剂，其有效地逆转突变型NPC缺陷。通过2BAct靶向ISR减轻了脑类器官和小鼠模型中的核糖体病缺陷。因此，我们的SNORD 118突变体类器官和小鼠重现了人脑核糖体病，并交叉验证了适应不良ISR作为一种关键的疾病驱动机制，指出了一种治疗干预策略。核糖体病的小鼠和脑类器官模型使得能够将整合的应激反应鉴定为治疗靶点。
Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell–based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy. Mouse and brain organoid models of ribosomopathy enable the identification of integrated stress response as a therapeutic target.
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影响因子：
4.6
作者：
Herrera, Salvador C.;Bach, Erika A.
通讯作者：
Bach, Erika A.
影响因子：
5.7
作者：
Quezada E;Cappelli C;Diaz I;Jury N;Wightman N;Brown RH Jr;Montecino M;van Zundert B
通讯作者：
van Zundert B
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
DOI：
10.1073/pnas.1408305111
发表时间：
2014-09-09
影响因子：
11.1
作者：
Kraushar, Matthew L.;Thompson, Kevin;Rasin, Mladen-Roko
通讯作者：
Rasin, Mladen-Roko