한빛사논문
- 조회568
Jee-Hyun Um1,2*, Dong Jin Shin1,2,3*, Se Myeong Choi4*, Alen Benhur Pravin Nathan5*, Young Yeon Kim1,2,3, Da Ye Lee1,2,3, Dae Jin Jeong1,2,3, Dong Hyun Kim6, Kyung Hwa Kim7, Young Hye Kim8, Jihoon Nah9, Jeong-hee Jeong10, Eunhee Yoo10, Hwa Kyoung Shin11, Hwan Tae Park1,3,12, Jihoon Jo5, Jong Hyun Cho3,4, Jeanho Yun1,2,3
1Peripheral Neuropathy Research Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
2Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea.
3Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea.
4Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea.
5Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
6Department of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul, Republic of Korea.
7Department of Health Sciences, The Graduate School of Dong-A University, 840 Hadan-dong, Saha-gu, Busan 49315, Republic of Korea.
8Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Chungbuk, 28119, Republic of Korea.
9Department of Biochemistry, Chungbuk National University, Cheongju, Republic of Korea.
10Altmedical Co., Ltd. Seoul, 02792, Republic of Korea.
11Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea.
12Department of Molecular Neuroscience, College of Medicine, Dong-A University, Busan, Republic of Korea.
*J.H. Um, D.J. Shin, S.M. Choi and A. Nathan contributed equally to this paper.
Corresponding authors: Jihoon Jo; Jong Hyun Cho; Jeanho Yun
Abstract
Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD.
Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects.
Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy.
Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-03)
- 국내 연구진
- 생명과학 > 세포생물학
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