이필휴 (연세대학교 의과대학)

한빛사논문

조회384

연세대학교 의과대학

CV File 184 kb

Proc. Natl. Acad. Sci. USA, Sep 12 2023, 120 (37) | https://doi.org/10.1073/pnas.2221929120 A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

Dong Yeol Kim^a, Jin Young Shin^a,b, Ji Eun Lee^a, Ha Na Kim^a, Seok Jong Chung^c, Han Soo Yoo^a, Sang Jin Kim^d, Hwa Jin Cho^e, Eun- Jae Lee^f, Soo Jeong Nam^g, Seong Heon Kim^h, Jaewon Jang^h, Seung Eun Leeⁱ, and Phil Hyu Lee^a,b,1

^aDepartment of Neurology, Yonsei University College of Medicine, Seoul 03722, South Korea;

^bDepartment of Biomedical Science, Yonsei University College of Medicine, Seoul 03722, South Korea;

^cDepartment of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin 16995, South Korea;

^dDepartment of Neurology, Inje University Busan Paik Hospital, Busan 47392, South Korea;

^eDepartment of Pathology, Inje University Busan Paik Hospital, Busan 47392, South Korea;

^fDepartment of Neurology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, South Korea;

^gDepartment of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, South Korea;

^hDepartment of Neurology, Kangwon National University Hospital, Chuncheon 24289, South Korea;

ⁱVirus Facility, Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, South Korea

¹To whom correspondence may be addressed. : Phil Hyu Lee

Abstract

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-07)
연구진국내 연구진
분야 의약학 > 신경의학

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