Dietary intake of alpha-ketoglutarate ameliorates alpha-synuclein pathology in mouse models of Parkinson's disease

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

作者地址："[Zhang, Wenlong; Ding, Liuyan; Mao, Hengxu; Xu, Pingyi] Guangzhou Med Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou 510120, Peoples R China; [Zhang, Wenlong; Ding, Liuyan; Zhang, Mengran; Zheng, Shaohui; Ma, Runfang; Gong, Junwei; Zhang, Yunlong] Guangzhou Med Univ, Sch Basic Med Sci, Key Lab Neurosci, Guangzhou 511436, Peoples R China; [Zhang, Mengran; Zheng, Shaohui; Ma, Runfang; Zhang, Yunlong] Westlake Univ, Sch Life Sci, Hangzhou 310024, Peoples R China; [Zhang, Mengran; Zheng, Shaohui; Ma, Runfang; Zhang, Yunlong] 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 Neurosci, Guangzhou 511436, Peoples R China.; Zhang, YL (通讯作者)，Westlake Univ, Sch Life Sci, Hangzhou 310024, Peoples R China.; Zhang, YL (通讯作者)，Westlake Lab Life Sci & Biomed, Hangzhou 310024, Peoples R China."

来源：CELLULAR AND MOLECULAR LIFE SCIENCES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000992783600001

JCR分区：Q1

影响因子：6.2

年份：2023

卷号：80

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：Parkinson's disease; AKG; DHA; alpha-synuclein; DA neuron degeneration; Gut-brain axis

摘要："Parkinson's disease (PD) is a progressive movement disorder characterized by dopaminergic (DA) neuron degeneration and the existence of Lewy bodies formed by misfolded a-synuclein. Emerging evidence supports the benefits of dietary interventions in PD due to their safety and practicality. Previously, dietary intake of a-ketoglutarate (AKG) was proved to extend the lifespan of various species and protect mice from frailty. However, the mechanism of dietary AKG's effects in PD remains undetermined. In the present study, we report that an AKG-based diet significantly ameliorated a-synuclein pathology, and rescued DA neuron degeneration and impaired DA synapses in adeno-associated virus (AAV)-loaded human a-synuclein mice and transgenic A53T a-synuclein (A53T a-Syn) mice. Moreover, AKG diet increased nigral docosahexaenoic acid (DHA) levels and DHA supplementation reproduced the anti-a-synuclein effects in the PD mouse model. Our study reveals that AKG and DHA induced microglia to phagocytose and degrade a-synuclein via promoting C1q and suppressed pro-inflammatory reactions. Furthermore, results indicate that modulating gut polyunsaturated fatty acid metabolism and microbiota Lachnospiraceae_NK4A136_group in the gut-brain axis may underlie AKG's benefits in treating a-synucleinopathy in mice. Together, our findings propose that dietary intake of AKG is a feasible and promising therapeutic approach for PD."

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

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