比较 HD knockin 猪和小鼠揭示了 IL-17 的病理作用。

Comparing HD knockin pigs and mice reveals the pathological role of IL-17.

机构信息

Guangdong Key Laboratory of Non-human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Institute of Neurological Diseases, North Sichuan Medical College, Nanchong 637000, China.

出版信息

Cell Rep. 2023 Dec 26;42(12):113443. doi: 10.1016/j.celrep.2023.113443. Epub 2023 Nov 20.

DOI:10.1016/j.celrep.2023.113443

PMID:37979175

Abstract

Our previous work has established a knockin (KI) pig model of Huntington's disease (HD) that can replicate the typical pathological features of HD, including selective striatal neuronal loss, reactive gliosis, and axonal degeneration. However, HD KI mice exhibit milder neuropathological phenotypes and lack overt neurodegeneration. By performing RNA sequencing to compare the gene expression profiles between HD KI pigs and mice, we find that genes related to interleukin-17 (IL-17) signaling are upregulated in the HD pig brains compared to the mouse brains. Delivery of IL-17 into the brain striatum of HD KI mice causes greater reactive gliosis and synaptic deficiency compared to HD KI mice that received PBS. These findings suggest that the upregulation of genes related to IL-17 signaling in HD pig brains contributes to severe glial pathology in HD and identify this as a potential therapeutic target for treating HD.

摘要

我们之前的工作建立了亨廷顿病（HD）的基因敲入（KI）猪模型，该模型可以复制 HD 的典型病理特征，包括选择性纹状体神经元丢失、反应性神经胶质增生和轴突变性。然而，HD KI 小鼠表现出较轻的神经病理学表型，并且缺乏明显的神经退行性变。通过进行 RNA 测序比较 HD KI 猪和小鼠之间的基因表达谱，我们发现与白细胞介素-17（IL-17）信号相关的基因在 HD 猪脑中上调，而在鼠脑中下调。将 IL-17 递送至 HD KI 小鼠的脑纹状体中会引起比接受 PBS 的 HD KI 小鼠更大的反应性神经胶质增生和突触缺失。这些发现表明，HD 猪脑中与 IL-17 信号相关的基因上调导致 HD 中的严重神经胶质病理学，并将其确定为治疗 HD 的潜在治疗靶点。