Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.
School of Biological Science, Seoul National University, Seoul, Republic of Korea.
J Cell Biol. 2020 Dec 7;219(12). doi: 10.1083/jcb.202004107.
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.
树突病理在各种神经退行性疾病（NDs）中经常观察到。虽然以前的研究确定了几种导致树突缺陷的致病介质，这些介质通过在 NDs 中丧失功能起作用，但潜在的致病机制在很大程度上仍未得到探索。在这里，我们寻找 NDs 中树突缺陷的其他致病贡献者，发现 Relish/NF-κB 是聚谷氨酰胺（polyQ）疾病和肌萎缩侧索硬化症（ALS）动物模型中基于毒性增益的树突缺陷的新型介质。在聚 Q 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 内切酶裂解，以产生 N 端片段 Rel68，随后 Charon 介导 Rel68 的核定位。Rel68 本身诱导神经元毒性，导致树突和行为缺陷，我们确定了两个新的转录靶标 Tup 和 Pros，它们介导 Rel68 诱导的神经元毒性。最后，我们表明 Rel68 诱导的毒性也导致 ALS 果蝇模型中的树突和行为缺陷。总之，我们的数据提出抑制 Relish/NF-κB 的潜在毒性作为 NDs 中树突病理的一种新的致病机制。
