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Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease

文献类型：期刊论文

作者Dong, Jianjian2,3; Xiang, Guanghai4; Xia, Xiaoxue2; Xu, Lewen2; Wen, Peihua2; Xu, Chenchen2; Xu, Yin2; Su, Yushuang5; Song, Yanze1; Tong, Haiyang6
刊名JOURNAL OF NEUROINFLAMMATION
出版日期2024-09-27
卷号21
关键词Wilson's disease ATP7B gene R778L point mutation Hepatic inflammation Neurological manifestations CRISPR/Cas9
DOI10.1186/s12974-024-03178-5
通讯作者Cheng, Nan(NanCheng111065@ahtcm.edu.cn) ; Wang, Haoyi(wanghaoyi@ioz.ac.cn) ; Zhou, Hong(hzhou@ahmu.edu.cn)
英文摘要Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3-5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD.
WOS关键词CHINESE PATIENTS ; MUTATIONS ; SPECTRUM ; PHENOTYPE ; GENOTYPE ; GENE ; MICE
资助项目Natural Science Foundation of Anhui Province
WOS研究方向Immunology ; Neurosciences & Neurology
语种英语
WOS记录号WOS:001325058700002
出版者BMC
资助机构Natural Science Foundation of Anhui Province
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/135643]  
专题中国科学院合肥物质科学研究院
通讯作者Cheng, Nan; Wang, Haoyi; Zhou, Hong
作者单位1.Chinese Acad Sci, Univ Chinese Acad Sci, Inst Zool, 1 Beichen West Rd, Beijing 100101, Peoples R China
2.Anhui Univ Chinese Med, Inst Neurol, 357 Changjiang Middle Rd, Hefei 230061, Anhui, Peoples R China
3.Anhui Univ Chinese Med, Ctr Xin An Med & Modernizat Tradit Chinese Med IHM, Hefei 230012, Peoples R China
4.Hefei Comprehens Natl Sci Ctr, Inst Hlth & Med, Key Lab Immune Response & Immunotherapy, Hefei 230601, Peoples R China
5.Anhui Med Univ, Sch Life Sci, Hefei 230032, Peoples R China
6.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Hefei 230031, Peoples R China
7.Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Peoples R China
推荐引用方式
GB/T 7714		 Dong, Jianjian,Xiang, Guanghai,Xia, Xiaoxue,et al. Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease[J]. JOURNAL OF NEUROINFLAMMATION,2024,21.
APA Dong, Jianjian.,Xiang, Guanghai.,Xia, Xiaoxue.,Xu, Lewen.,Wen, Peihua.,...&Zhou, Hong.(2024).Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease.JOURNAL OF NEUROINFLAMMATION,21.
MLA Dong, Jianjian,et al."Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease".JOURNAL OF NEUROINFLAMMATION 21(2024).

入库方式： OAI收割

来源：合肥物质科学研究院

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