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Theranostics, 2025-3-31; 15(11):4890-4908 | doi:10.7150/thno.10595
Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection
Soo-Jin Oh1, Young Yeon Kim2, Ruiying Ma1,3, Seok Tae Choi4, Se Myeong Choi5, Jong Hyun Cho5, Ji-Yeun Hur6, Yongjin Yoo1,3, Kihoon Han1,3, Hosun Park4, Jeanho Yun2, Ok Sarah Shin1,7
1BK21 Graduate Program, Department of Biomedical Sciences, College of Medicine, Seoul, Republic of Korea.
2Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea.
3Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea.
4Department of Microbiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
5Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea.
6Department of Biological Sciences, Ajou University, Suwon, Republic of Korea.
7Department of Convergence medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
Corresponding authors: Ok Sarah Shin, and Jeanho Yun
1BK21 Graduate Program, Department of Biomedical Sciences, College of Medicine, Seoul, Republic of Korea.
2Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Republic of Korea.
3Department of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea.
4Department of Microbiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
5Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea.
6Department of Biological Sciences, Ajou University, Suwon, Republic of Korea.
7Department of Convergence medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
Corresponding authors: Ok Sarah Shin, and Jeanho Yun
Abstract
Rationale: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of dysfunctional mitochondria. Herpes simplex virus type 1 (HSV1) may be a risk factor for the neuropathology linked to amyloid β (Aβ) accumulation. However, the mechanisms underlying HSV1-associated mitochondrial dysfunction in AD remain unclear. ALT001 is a novel drug that ameliorates AD-related cognitive impairment via ULK1/Rab9-mediated alternative mitophagy. In this study, we investigated the effects of ALT001 on the neurodegeneration-related microglial signatures associated with HSV1 infection.
Methods: Molecular mechanisms and physiological functions of mitophagy was investigated in HSV1-infected microglia, including primary murine and human embryonic stem cell (ESC)-derived microglia (ES-MG), as well as in a microglia-neuron co-culture system. Microglial gene signatures following HSV1 infection in the presence or absence of ALT001 were analyzed using bulk RNA sequencing, and the effects of ALT001 on microglial phagocytosis and microglia-mediated immune responses were further evaluated by flow cytometry and cytokine profiles.
Results: HSV1 infection inhibited PINK1/Parkin-mediated mitophagy via HSV1-encoded protein kinase US3, resulting in mitochondrial dysfunction in both human and mouse microglia. Furthermore, transcriptomic analysis of HSV1-infected microglia revealed an upregulation of distinct microglial genes associated with disease-associated microglia (DAM)-like phenotype and pro-inflammatory activity. Pharmacological targeting of mitophagy using ALT001 prevents mitochondrial damage caused by HSV1 through ULK1/Rab9-mediated pathway. Furthermore, ALT001-induced ULK1/Rab9-dependent mitophagy restricts HSV1 infection by activating interferon-mediated antiviral immunity. Consequently, ALT001 reduces HSV1-triggered neuroinflammation, recovers HSV1-altered microglial phagocytosis for Aβ, and efficiently reverses morphological and molecular abnormalities in HSV1-infected microglia by triggering mitophagy in ES-MG. ALT001 also suppressed HSV1-mediated Aβ accumulation and neurodegeneration in the microglia-neuron co-culture and cerebral organoid model.
Conclusions: In this study, we identified a critical molecular link between HSV1 and AD-related microglial dysfunction. Furthermore, our findings provide an evidence that therapeutic targeting of alternative mitophagy via ALT001 effectively interfere with HSV1-induced microglial dysfunction and alleviate neurodegeneration.
Methods: Molecular mechanisms and physiological functions of mitophagy was investigated in HSV1-infected microglia, including primary murine and human embryonic stem cell (ESC)-derived microglia (ES-MG), as well as in a microglia-neuron co-culture system. Microglial gene signatures following HSV1 infection in the presence or absence of ALT001 were analyzed using bulk RNA sequencing, and the effects of ALT001 on microglial phagocytosis and microglia-mediated immune responses were further evaluated by flow cytometry and cytokine profiles.
Results: HSV1 infection inhibited PINK1/Parkin-mediated mitophagy via HSV1-encoded protein kinase US3, resulting in mitochondrial dysfunction in both human and mouse microglia. Furthermore, transcriptomic analysis of HSV1-infected microglia revealed an upregulation of distinct microglial genes associated with disease-associated microglia (DAM)-like phenotype and pro-inflammatory activity. Pharmacological targeting of mitophagy using ALT001 prevents mitochondrial damage caused by HSV1 through ULK1/Rab9-mediated pathway. Furthermore, ALT001-induced ULK1/Rab9-dependent mitophagy restricts HSV1 infection by activating interferon-mediated antiviral immunity. Consequently, ALT001 reduces HSV1-triggered neuroinflammation, recovers HSV1-altered microglial phagocytosis for Aβ, and efficiently reverses morphological and molecular abnormalities in HSV1-infected microglia by triggering mitophagy in ES-MG. ALT001 also suppressed HSV1-mediated Aβ accumulation and neurodegeneration in the microglia-neuron co-culture and cerebral organoid model.
Conclusions: In this study, we identified a critical molecular link between HSV1 and AD-related microglial dysfunction. Furthermore, our findings provide an evidence that therapeutic targeting of alternative mitophagy via ALT001 effectively interfere with HSV1-induced microglial dysfunction and alleviate neurodegeneration.
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- Research article
- 2025년 03월 (BRIC 등록일 2025-04-09)
- 국내 연구진
- 의약학 > 감염의학
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