NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases.
NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases.
复制标题
DOI：
10.1083/jcb.202004107
复制
发表时间：
2020-12-07
期刊：
影响因子：
--
通讯作者：
Lee SB
中科院分区：
文献类型：
--
作者：
Han MH;Kwon MJ;Ko BS;Hyeon DY;Lee D;Kim HJ;Hwang D;Lee SB
树突病理是神经退行性疾病的一个突出的早期特征。Han等人使用果蝇的树突状树枝状神经元表明，Relish/NF-κB通过转录上调Tup而导致多聚谷氨酰胺疾病和肌萎缩侧索硬化症动物模型中的树突和行为缺陷。在各种神经退行性疾病（ND）中经常观察到树突病理。虽然以前的研究确定了几个致病介质的树突缺陷，通过功能丧失的ND，潜在的致病机制仍然在很大程度上未被探索。在这里，我们的搜索在ND树突缺陷的其他致病因素确定Relish/NF-κB作为一种新的获得毒性为基础的介质的树突缺陷的动物模型中的多聚谷氨酰胺（polyQ）疾病和肌萎缩侧索硬化症（ALS）。在polyQ疾病的果蝇模型中，polyQ诱导的树突缺陷需要Dredd/Caspase-8介导的Relish内切蛋白水解切割以产生N-末端片段Rel 68，以及随后的Charon介导的Rel 68核定位。Rel 68单独诱导神经元毒性引起树突和行为缺陷，我们确定了两个新的转录靶点，Tup和Pros，介导Rel 68诱导的神经元毒性。最后，我们表明，Rel 68诱导的毒性也有助于树突和行为缺陷的果蝇模型ALS。总的来说，我们的数据提出解除抑制的潜在毒性的Relish/NF-κB作为一种新的致病机制的树突病理学在ND。
Dendrite pathology is a prominent early feature of neurodegenerative diseases. Using dendritic arborization neurons of Drosophila, Han et al. show that Relish/NF-κB contributes to dendrite and behavioral defects in animal models for polyglutamine diseases and amyotrophic lateral sclerosis via transcriptionally upregulating Tup. Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss of function in NDs, the underlying pathogenic mechanisms remain largely unexplored. Here, our search for additional pathogenic contributors to dendrite defects in NDs identifies Relish/NF-κB as a novel gain-of-toxicity–based mediator of dendrite defects in animal models for polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for polyQ diseases, polyQ-induced dendrite defects require Dredd/Caspase-8–mediated endoproteolytic cleavage of Relish to generate the N-terminal fragment, Rel68, and subsequent Charon-mediated nuclear localization of Rel68. Rel68 alone induced neuronal toxicity causing dendrite and behavioral defects, and we identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, we show that Rel68-induced toxicity also contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, our data propose disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.
登录
查看更多内容
影响因子：
20.3
作者：
Hinz, M;Löser, P;Scheidereit, C
通讯作者：
Scheidereit, C
影响因子：
4.1
作者：
Helenius, M;Hanninen, M;Salminen, A
通讯作者：
Salminen, A
影响因子：
11.1
作者：
Blumenstock S;Rodrigues EF;Peters F;Blazquez-Llorca L;Schmidt F;Giese A;Herms J
通讯作者：
Herms J
影响因子：
56.9
作者：
GRAVELAND, GA;WILLIAMS, RS;DIFIGLIA, M
通讯作者：
DIFIGLIA, M
DOI：
10.1073/pnas.1110666109
发表时间：
2012-03-06
影响因子：
11.1
作者：
Chinchore, Yashodhan;Gerber, Gloria F.;Dolph, Patrick J.
通讯作者：
Dolph, Patrick J.