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Addition of a-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems

文献类型：期刊论文

作者Yang, Ze-xian4,5; Zhang, Yu3,5; Wang, Qing4,5; Zhang, Lei5; Liu, Yi-fei5; Zhang, Ye4,5; Ren, Yu5; Zhou, Chen2; Gao, Hui-wen1,3; Zhang, Nai-xia2,4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-09-08
页码16
关键词Parkinson's disease gut-brain axis a-Synuclein inflammation microbiota intestinal mouse coloclysis model
ISSN号1671-4083
DOI10.1038/s41401-023-01150-2
通讯作者Zhang, Yu(zhangyu5@simm.ac.cn) ; Zhang, Nai-xia(nxzhang@simm.ac.cn) ; Feng, Lin-yin(lyfeng@simm.ac.cn)
英文摘要The gut-brain axis plays a vital role in Parkinson's disease (PD). The mechanisms of gut-brain transmission mainly focus on asynuclein deposition, intestinal inflammation and microbiota function. A few studies have shown the trigger of PD pathology in the gut. a-Synuclein is highly conserved in food products, which was able to form beta-folded aggregates and to infect the intestinal mucosa. In this study we investigated whether a-synuclein-preformed fibril (PFF) exposure could modulate the intestinal environment and induce rodent models replicating PD pathology. We first showed that PFF could be internalized into co-cultured Caco-2/HT29/Raji b cells in vitro. Furthermore, we demonstrated that PFF perfusion caused the intestinal inflammation and activation of enteric glial cells in an ex vivo intestinal organ culture and in an in vivo intestinal mouse coloclysis model. Moreover, we found that PFF exposure through regular coloclysis induced PD pathology in wild-type (WT) and A53T alpha-synuclein transgenic mice with various phenotypes. Particularly in A53T mice, PFF induced significant behavioral disorders, intestinal inflammation, asynuclein deposition, microbiota dysbiosis, glial activation as well as degeneration of dopaminergic neurons in the substantia nigra. In WT mice, however, the PFF induced only mild behavioral abnormalities, intestinal inflammation, alpha-synuclein deposition, and glial activation, without significant changes in microbiota and dopaminergic neurons. Our results reveal the possibility of alpha-synuclein aggregates binding to the intestinal mucosa and modeling PD in mice. This study may shed light on the investigation and early intervention of the gut-origin hypothesis in neurodegenerative diseases.
WOS关键词PATHOLOGICAL ALPHA-SYNUCLEIN ; DISEASE
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-003-013] ; Scientific Innovation Project of the Chinese Academy of Sciences[XDA12040304] ; Scientific Innovation Project of the Chinese Academy of Sciences[XDA12040216] ; Shanghai Committee of Science and Technology, China[18DZ2290200] ; National Natural Science Foundation of China[82104140] ; National Natural Science Foundation of China[32171220]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001064350600001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/307297]  
专题中国科学院上海药物研究所
通讯作者Zhang, Yu; Zhang, Nai-xia; Feng, Lin-yin
作者单位1.Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Minist Educ, Qingdao 266003, Peoples R China
2.Chinese Acad Sci, Analyt Res Ctr Organ & Biol Mol, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery CNPRDD, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Ze-xian,Zhang, Yu,Wang, Qing,et al. Addition of a-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems[J]. ACTA PHARMACOLOGICA SINICA,2023:16.
APA Yang, Ze-xian.,Zhang, Yu.,Wang, Qing.,Zhang, Lei.,Liu, Yi-fei.,...&Feng, Lin-yin.(2023).Addition of a-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems.ACTA PHARMACOLOGICA SINICA,16.
MLA Yang, Ze-xian,et al."Addition of a-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems".ACTA PHARMACOLOGICA SINICA (2023):16.

入库方式： OAI收割

来源：上海药物研究所

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