최진규 (경희대학교, 현 엠테라파마)

한빛사논문

조회319

경희대학교, 현 엠테라파마

CV File 411 kb

EBioMedicine, Nov 22 2023, 98 S2352-3964(23)00453-X | https://doi.org/10.1016/j.ebiom.2023.104887 P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration

Eugene Huh,^a,b,l,m Jin Gyu Choi,^a,l,n Yujin Choi,^c In Gyoung Ju,^a,b Bora Kim,^b Yoon-Jung Shin,^b Jong Min An,^dMyoung Gyu Park,^e Sung Vin Yim,^f Su Jin Chung,^g Sang-Uk Seo,^h Dokyoung Kim,^d,i Chun Hyung Kim,^j Dong Hyun Kim,^b and Myung Sook Oh^a,b,c,k,∗

^aDepartment of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^bNeurobiota Research Center, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^cDepartment of Biochemical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemungu, Seoul, 02447, Republic of Korea

^dDepartment of Biomedical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^eMetaCen Therapeutics Inc. R&D Center, 256 Changryongdae-ro, Yeongtong-gu, Suwon-si, Gyeonggi-Do, 16229, Republic of Korea

^fDepartment of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^gDepartment of Neurology, Myongji Hospital, Hanyang University College of Medicine, 155 Hwasu-ro, Deokyang-gu, Goyang-si, Gyeonggi-Do, 10475, Republic of Korea

^hDepartment of Microbiology, College of Medicine, The Catholic University of Korea, 222 Banpodae-ro, Seocho-gu, Seoul, 06591, Republic of Korea

ⁱDepartment of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^jPaean Biotechnology, 17 Techno 4-ro, Yuseong-gu, Daejeon, 34013, Republic of Korea

^kDepartment of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea

^*Corresponding author: M.S. Oh

^lThese authors have contributed equally to this work.

^mCurrent address: Department of Formulae Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujung-Gu, Seongnam, Gyeonggi-Do, 13120, Republic of Korea.

ⁿCurrent address: MThera Pharma Co., 1 Magokjungang 8-ro, Gangseo-gu, Seoul, 07793, Republic of Korea.

Abstract

Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain. We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro. The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells. Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis. This study was supported by a grant from the National Research Foundation of Korea.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-27)
연구진국내 연구진
분야 의약학 > 약학

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