Cntnap4 partial deficiency exacerbates alpha-synuclein pathology through astrocyte-microglia C3-C3aR pathway

作者全名："Zhang, Wenlong; Ding, Liuyan; Chen, Huaqing; Zhang, Mengran; Ma, Runfang; Zheng, Shaohui; Gong, Junwei; Zhang, Zhiling; Xu, Huaxi; Xu, Pingyi; Zhang, Yunlong"

作者地址："[Zhang, Wenlong; Ding, Liuyan; Zhang, Zhiling; Xu, Pingyi] Guangzhou Med Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou 510120, Peoples R China; [Zhang, Wenlong; Ding, Liuyan; Zhang, Mengran; Ma, Runfang; Zheng, Shaohui; Gong, Junwei; Zhang, Yunlong] Guangzhou Med Univ, Sch Basic Med Sci, Key Lab Neurol Funct & Hlth, Guangzhou 511436, Peoples R China; [Chen, Huaqing] Tsinghua Univ, Inst Biopharmaceut & Hlth Engn,State Key Lab Hlth, Ctr Biotechnol & Biomed,State Key Lab Chem Oncogen, Shenzhen Int Grad Sch,Shenzhen Key Lab Gene & Anti, Shenzhen 518055, Guangdong, Peoples R China; [Zhang, Mengran; Ma, Runfang; Zheng, Shaohui; Zhang, Yunlong] Westlake Univ, Sch Life Sci, Westlake Lab Life Sci & Biomed, Hangzhou 310024, Peoples R China; [Xu, Huaxi] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China"

通信作者："Xu, PY (通讯作者)，Guangzhou Med Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou 510120, Peoples R China.; Zhang, YL (通讯作者)，Guangzhou Med Univ, Sch Basic Med Sci, Key Lab Neurol Funct & Hlth, Guangzhou 511436, Peoples R China.; Zhang, YL (通讯作者)，Westlake Univ, Sch Life Sci, Westlake Lab Life Sci & Biomed, Hangzhou 310024, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000975665700002

JCR分区：Q1

影响因子：9

年份：2023

卷号：14

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic alpha-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates alpha-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human alpha-synuclein overexpression (AAV-h alpha-Syn). This scenario was further validated in A53T alpha-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, alpha-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte-microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated alpha-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in alpha-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment."

基金机构："National Natural Science Foundation of China [82174468, 82071416, 81870992, 81870856, 82101325]; Science and Technology Planning Project of Guangzhou [201904010238]; Guangzhou Medical University Discipline Construction Funds [JCXKJS2022A09]; Central government guiding local science and technology development projects [ZYYD2022C17]; Key Research and Development Program of Guangzhou [2023B03J0631]; Municipal University (Faculty) [202102010010]; Guangdong Basic and Applied Basic Research Foundation [2022B1515230004]; China Postdoctoral Science Foundation [2021M700951]; Postdoctoral Startup Foundation of Guangzhou"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 82174468 to YLZ, No. 82071416, 81870992, 81870856 to PYX, No. 82101325 to WLZ), the Science and Technology Planning Project of Guangzhou (No. 201904010238 to YLZ), Guangzhou Medical University Discipline Construction Funds (Basic Medicine, No. JCXKJS2022A09 to YLZ), Central government guiding local science and technology development projects (ZYYD2022C17 to PYX), Key Research and Development Program of Guangzhou (No. 2023B03J0631 to PYX), Municipal University (Faculty) joint funding project (No. 202102010010 to PYX), Guangdong Basic and Applied Basic Research Foundation (No. 2022B1515230004 to PYX), the China Postdoctoral Science Foundation (No. 2021M700951 to WLZ), and Postdoctoral Startup Foundation of Guangzhou (WLZ)."