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Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

Neural Regeneration research 2025年第11期20卷 3193-3206页

作者： Ling-Xiao Yi Hui Ren Woon Genevieve Saw Li Zeng Eng King Tan Zhi Dong Zhou National Neuroscience Institute Singapore Nanyang Technology University Singapore Department of Neurology Singapore General HospitalSingapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Medical SchoolSingapore

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative *** the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and *** induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease *** current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem *** benefits of induced pluripotent stem cell-based research are *** dopaminergic neuron differentiation protocols from induced pluripotent stem cells are *** emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are ***,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

关键词： dopaminergic neurons induced pluripotent stem cells Parkinson's disease stem cell approaches

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Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability

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Life Metabolism 2025年第1期4卷 17-34页

作者： Yik-Lam Cho Hayden Weng Siong Tan Jicheng Yang Basil Zheng Mian Kuah Nicole Si Ying Lim Naiyang Fu Boon-Huat Bay Shuo-Chien Ling Han-Ming Shen Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117593Singapore Department of Anatomy Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117594Singapore Cancer and Stem Cell Biology Program Duke-NUS Medical SchoolSingapore 169857Singapore NUS Centre for Cancer Research Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore Programs in Neuroscience and Behavioral Disorders Duke-NUS Medical SchoolSingapore 169857Singapore Healthy Longevity Translational Research Programme Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117549Singapore Faculty of Health Sciences MOE Frontier Centre for Precision OncologyUniversity of MacaoMacao 999078China

Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the pentose phosphate pathway(PPP)in *** metabolism is closely implicated in the regulation of mitophagy,a selective form of autophagy for the degradation of damaged *** PPP and its key enzymes such as G6PD possess important metabolic functions,including biosynthesis and maintenance of intracellular redox balance,while their implication in mitophagy is largely ***,via a whole-genome CRISPR-Cas9 screening,we identified that G6PD regulates PINK1(phosphatase and tensin homolog[PTEN]-induced kinase 1)-Parkinmediated *** function of G6PD in mitophagy was verified via multiple approaches.G6PD deletion significantly inhibited mitophagy,which can be rescued by G6PD ***,while the catalytic activity of G6PD is required,the known PPP functions per se are not involved in mitophagy ***,we found a portion of G6PD localized at mitochondria where it interacts with PINK1.G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation,a key starting point of ***,we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization,indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial *** summary,our study reveals a novel role of G6PD as a key positive regulator in mitophagy,which bridges several important cellular processes,namely glucose metabolism,redox homeostasis,and mitochondrial quality control.

关键词： G6PD mitophagy PINK1 ROS NADPH PPP

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Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges

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Pharmacological research 2025年 216卷 107770页

作者： Zhou, Zhi Dong Yi, Lingxiao Popławska-Domaszewicz, Karolina Chaudhuri, Kallol Ray Jankovic, Joseph Tan, Eng King National Neuroscience Institute of Singapore 11 Jalan Tan Tock Seng 308433 Singapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Medical School 8 College Road 169857 Singapore Department of Neurology Poznan University of Medical Sciences Poznan 60-355 Poland Parkinson's Foundation Centre of Excellence King's College Hospital Denmark Hill London SE5 9RS United Kingdom Department of Basic and Clinical Neuroscience The Maurice Wohl Clinical Neuroscience Institute King's College London Cutcombe Road London SE5 9RT United Kingdom Parkinson's Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston TX United States

Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects. © 2025 The Authors

关键词： Alzheimer's disease GLP-1 receptor agonists Glucagon-like peptide-1 Neurodegenerative diseases Parkinsons' disease Type 2 diabetes mellitus

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Sociodemographic influences on substance use in psychosis in an African cohort

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Schizophrenia research 2025年 281卷 157-163页

作者： Campbell, Megan L. Odokonyero, Raymond Akena, Dickens Alemayehu, Melkam Atwoli, Lukoye Chibnik, Lori B. Gelaye, Bizu Gichuru, Stella Kariuki, Symon M. Koenen, Karestan C. Kwobah, Edith Kyebuzibwa, Joseph Mwema, Rehema M. Newton, Charles R.J.C. Post, Kristianna Pretorius, Adele Stevenson, Anne Stroud, Rocky E. Teferra, Solomon Zingela, Zukiswa Stein, Dan J. Hook, Kimberly Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER) Program Harvard T.H. Chan School of Public Health and the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT United States SAMRC Unit on Risk & Resilience in Mental Disorders Department of Psychiatry Neuroscience Institute University of Cape Town South Africa Department of Psychiatry School of Medicine College of Health Sciences Makerere University Uganda Department of Psychiatry School of Medicine College of Health Sciences Addis Ababa University Ethiopia Neuroscience Unit KEMRI-Wellcome Trust Research Program Kenya Stanley Center for Psychiatric Research Broad Institute of Harvard and MIT United States Department of Epidemiology Harvard T. H. Chan School of Public Health United States Department of Neurology Massachusetts General Hospital Harvard Medical School United States Department of Psychiatry Massachusetts General Hospital Harvard Medical School United States Department of Social and Behavioral Sciences Harvard T.H. Chan School of Public Health United States Department of Mental Health Moi Teaching and Referral Hospital Eldoret Kenya Department of Psychiatry University of Oxford United Kingdom Department of Psychiatry Faculty of Medicine and Health Sciences Stellenbosch University South Africa Executive Dean's Office Faculty of Health Sciences Nelson Mandela University South Africa

Background: Substance use is common among individuals with psychotic disorders, but limited research exists on the variations in substance use across countries in Africa. This study aims to investigate the frequency of alcohol, tobacco, cannabis, and khat consumption in individuals with bipolar disorder (BD) and schizophrenia (SCZ) across four African countries: South Africa, Ethiopia, Kenya, and Uganda. Methods: We utilized data from the Neuropsychiatric Genetics of African Populations-Psychosis project, a large case-control study which will soon have genetic data on over 42,000 participants, half with psychosis. Information on substance use was collected using the Alcohol, Smoking and Substance Involvement Screening Test v3 (ASSIST). The outcome was categorized into never (lifetime usage, no), irregular usage (weekly or monthly) and regular (daily use) based on reported frequency in the past three months. Each substance was modeled individually as an outcome in ordinal regression model adjusting for demographic factors of sex, education and country. Stratified analyses were performed to assess country-specific effects. Results: Individuals with BD had significantly higher odds of alcohol consumption compared to those with SCZ. Males showed higher odds of alcohol, tobacco, and khat consumption compared to females. Significant variations in alcohol, tobacco, and cannabis consumption were observed across different study countries. Education level was significantly associated with khat consumption, with higher education levels associated with lower odds of consumption. Conclusion: Country and sex-specific differences in substance use behaviors exist in a large-scale African case-control study of people with psychosis. The findings here are in line with previous work regarding sex and regional differences, though they differ from studies conducted in US populations in that minimal evidence was found to support a relationship between level of education and frequency of

关键词： African cohort Bipolar disorder Psychosis Schizophrenia Substance use

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Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson’s disease

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Translational Neurodegeneration 2019年第1期8卷 63-76页

作者： Zhi Dong Zhou Thevapriya Selvaratnam Ji Chao Tristan Lee Yin Xia Chao Eng-King Tan Department of Research National Neuroscience Institute11 Jalan Tan Tock SengSingapore 308433Singapore Department of Neurology Singapore General HospitalOutram RoadSingapore 169608Singapore Signature Research Program in Neuroscience and Behavioural Disorders Duke-NUS Medical School Singapore8 College RoadSingaporeSingapore

Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain *** detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in ***,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional *** is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and *** protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in *** recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been *** potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

关键词： Molecular targets Neuron degeneration Parkinson’s disease Protein aggregation Protein translation Proteostasis

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Role of dopamine in the pathophysiology of Parkinson’s disease

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Translational Neurodegeneration 2023年第1期12卷 281-295页

作者： Zhi Dong Zhou Ling Xiao Yi Dennis Qing Wang Tit Meng Lim Eng King Tan National Neuroscience Institute of Singapore 11 Jalan Tan Tock SengSingapore 308433Singapore Department of Neurology Singapore General HospitalOutram RoadSingapore 169608Singapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Graduate Medical School Singapore8 College RoadSingapore 169857Singapore Department of Neurology Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China Department of Biological Science National University of SingaporeSingapore 119077Singapore

A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD *** is the neurotransmitter of dopaminergic *** evidence suggests that DA interacts with environmental and genetic factors to contribute to PD *** of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD *** is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,*** we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.

关键词： Dopamine Dopamine quinones 3,4-Dihydroxyphenylacetaldehyde Neurodegeneration Pathogenesis Parkinson’s disease Reactive oxygen species Therapeutic strategies

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Corrigendum to ’ The role of ultrasonic vocalizations in rat laryngological investigations’ [Physiology & Behavior volume 294 (2025) start page 1 –end page 10 /article number 114887]

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Physiology and Behavior 2025年 295卷 114907-114907页

作者： Shembel, Adrianna C. Johnson, Aaron M. Ciucci, Michelle R. Lunaris, Charlie Lenell Morrison, Robert A. Rudisch, Denis Michael School of Behavioral and Brain Sciences University of Texas at Dallas Dallas TX United States Department of Otolaryngology-Head and Neck Voice Center University of Texas Southwestern Medical Center Dallas TX United States Department of Otolaryngology—Head and Neck Surgery NYU Voice Center NYU Langone Health New York NY United States Department of Surgery Division of Otolaryngology-Head & Neck Surgery UW School of Medicine and Public Health University of Wisconsin-Madison Madison WI United States Department of Communication Sciences and Disorders University of Wisconsin-Madison Madison WI United States Neuroscience Training Program University of Wisconsin-Madison Madison WI United States Communication Sciences and Disorders University of Northern Colorado Greeley CO United States Institute for Clinical and Translational Research UW School of Medicine and Public Health University of Wisconsin-Madison Madison WI United States

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Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD

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Brain, Behavior, and Immunity 2025年 128卷 540-548页

作者： Smith, Alicia K. Katrinli, Seyma Maihofer, Adam X. Aiello, Allison E. Baker, Dewleen G. Boks, Marco P. Brick, Leslie A. Chen, Chia-Yen Dalvie, Shareefa Fani, Negar Fortier, Catherine B. Gelernter, Joel Geuze, Elbert Gillespie, Charles F. Hayes, Jasmeet P. Hong, Suzi Kessler, Ronald C. King, Anthony P. Koen, Nastassja Koenen, Karestan C. Liberzon, Israel Linnstaedt, Sarah D. McLean, Samuel A. Michopoulos, Vasiliki Milberg, William P. Miller, Mark W. Mufford, Mary S. Nugent, Nicole R. Orcutt, Holly K. Powers, Abigail Rauch, Sheila A.M. Ressler, Kerry J. Risbrough, Victoria B. Rutten, Bart P.F. Smoller, Jordan W. Stein, Dan J. Stein, Murray B. Ursano, Robert J. Verfaellie, Mieke H. Vermetten, Eric Vinkers, Christiaan H. Wani, Agaz H. WareVinkers, Erin B. Wildman, Derek E. Wolf, Erika J. Zhao, Ying Logue, Mark W. Nievergelt, Caroline M. Uddin, Monica Zannas, Anthony S. Emory University Department of Gynecology and Obstetrics Atlanta GA United States Emory University Department of Human Genetics Atlanta GA United States Emory University Department of Psychiatry and Behavioral Sciences Atlanta GA United States University of California San Diego Department of Psychiatry La Jolla CA United States Veterans Affairs San Diego Healthcare System Center of Excellence for Stress and Mental Health San Diego CA United States Veterans Affairs San Diego Healthcare System Research Service San Diego CA United States Columbia University Robert N Butler Columbia Aging Center Department of Epidemiology New York NY United States Amsterdam UMC Department of Psychiatry NH Amsterdam Netherlands Dimence Specialised Mental Health Mood Disorders OV Deventer Netherlands University Medical Center Utrecht Department Psychiatry UT Utrecht Netherlands Alpert Medical School of Brown University Department of Psychiatry and Human Behavior Providence RI United States Biogen Inc. Translational Medicine Cambridge MA United States University of Cape Town Division of Human Genetics Western Province Cape Town South Africa Harvard Medical School Department of Psychiatry Boston MA United States VA Boston Healthcare System Geriatric Research Education and Clinical Center (GRECC) Boston MA United States VA Boston Healthcare System Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) Boston MA United States VA Connecticut Healthcare Center Psychiatry Service West Haven CT United States Yale University School of Medicine Departments of Psychiatry Genetics and Neuroscience New Haven CT United States Netherlands Ministry of Defence Brain Research and Innovation Centre UT Utrecht Netherlands UMC Utrecht Brain Center Rudolf Magnus Department of Psychiatry UT Utrecht Netherlands The Ohio State University Department of Psychology Columbus OH United States University of California San Diego Herbert Wertheim Sch

Background: Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD. Methods: This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics. Results: PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001). Conclusions: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD. © 2025 The Author(s)

关键词： B-cells CRP DNA methylation EWAS Immune Inflammation PTSD Trauma

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Study protocol for a randomized, placebo-controlled, double-masked mechanistic clinical trial of transdermal estrogen replacement in hypoestrogenic eating disorders to explore the role of estrogen on cognitive flexibility and reward processing

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Contemporary Clinical Trials 2025年 154卷 107924-107924页

作者： Breithaupt, Lauren Slattery, Meghan Lauze, Meghan Petterway, Felicia Lindman, Lauren Cravitz, Mia Naticchia, Sarah Seenivasa, Siddarth Powers, Macy Javaras, Kristin N. Alperovitz, David J. Halperin, Judith Dechant, Esther Thomas, Jennifer J. Lawson, Elizabeth A. Lee, Hang Pizzagalli, Diego A. Romer, Adrienne L. Kumar, Poornima Plessow, Franziska Misra, Madhusmita Eddy, Kamryn T. Department of Psychiatry Massachusetts General Hospital Boston MA United States Eating Disorders Clinical and Research Program Massachusetts General Hospital MA United States Mass General Brigham Multidisciplinary Eating Disorders Research Collaborative Mass General Brigham Boston MA United States Psychiatry Neuroimaging Laboratory Department of Psychiatry Brigham and Women's Hospital Harvard Medical School Boston MA United States Department of Psychiatry Harvard Medical School Boston MA United States Neuroendocrine Unit Massachusetts General Hospital Harvard Medical School MA United States Harvard University Department of Neuroscience Cambridge MA United States Division of Women's Mental Health McLean Hospital Belmont MA United States Klarman Eating Disorders Center McLean Hospital Belmont MA United States Department of Medicine Harvard Medical School Boston MA United States Division of Biostatistics Massachusetts General Hospital Boston MA United States Center for Depression Anxiety and Stress Research McLean Hospital Belmont MA United States McLean Imaging Center McLean Hospital Belmont MA United States Department of Psychology Virginia Polytechnic Institute and State University Blacksburg VA United States Department of Psychiatry and Behavioral Sciences Weill Institute for Neurosciences University of California San Francisco San Francisco CA United States Department of Pediatrics University of Virginia School of Medicine Charlottesville VA United States

Background: Restrictive eating disorders (EDs) are associated with cognitive inflexibility, reduced reward responsiveness, and tendency to favor delayed rewards, which contribute to illness maintenance and poor outcomes. Low estrogen is common in EDs and has been linked to poor cognitive flexibility and reward processing in other conditions. We describe a randomized controlled double-masked trial of short-term (12 weeks) transdermal estrogen (100 μg 17-β) replacement versus placebo to test estrogen-effects on cognitive flexibility, reward responsiveness, delay discounting, and ED pathology in females with EDs and low estrogen (ED-LE). Methods: Participants will include N = 120 females with ED-LE (14–35 years) with clinical, neuropsychological, and neural assessments occurring at baseline, eight weeks, and 12 weeks. Results: Primary outcomes will include between-group differences in 8-week change in cognitive flexibility, reward responsiveness, and delay discounting, and between-group differences in 12-week change in ED pathology. Secondary outcomes will include between-group differences in 8-week change in neural activation during cognitive flexibility and reward-related functional magnetic resonance imaging paradigms and mediation effects of 8-week change in cognitive flexibility, reward responsiveness, and delay discounting on 12-week change in ED pathology. Conclusion: We hypothesize that estrogen replacement will (1) increase cognitive flexibility, reward responsiveness, and delay discounting, and (2) reduce ED pathology;and (3) 8-week changes in cognitive flexibility, reward responsiveness, and delay discounting will mediate 12-week changes in ED pathology. These data will systematically probe the role of estrogen in key neurocognitive features associated with poor ED outcomes to guide development of novel interventions for this population. © 2024

关键词： Anorexia nervosa Atypical anorexia nervosa Cognitive flexibility Delay discounting Eating disorder Estrogen Reward responsiveness

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FOXO-regulated DEAF1 controls muscle regeneration through autophagy

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Autophagy 2024年第12期20卷 2632-2654页

作者： Goh, Kah Yong Lee, Wen Xing Choy, Sze Mun Priyadarshini, Gopal Krishnan Chua, Kenon Tan, Qian Hui Low, Shin Yi Chin, Hui San Wong, Chee Seng Huang, Shu-Yi Fu, Nai Yang Nishiyama, Jun Harmston, Nathan Tang, Hong-Wen Program in Cancer and Stem Cell Biology Duke-NUS Medical School Department of Orthopaedic Surgery Singapore General Hospital Programme in Musculoskeletal Sciences Academic Clinical Program SingHealth/Duke-NUS Division of Science Yale-NUS College Program in Neuroscience and Behavioral Disorders Duke-NUS Medical School Department of Medical Research National Taiwan University Hospital Molecular Biosciences Division Cardiff School of Biosciences Cardiff University Division of Cellular & Molecular Research Humphrey Oei Institute of Cancer Research National Cancer Centre Singapore

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1)–a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy. Abbreviations: DEAF1: Deformed epidermal autoregulatory factor-1;FOXO: Forkhead box O;MuSC: Muscle Stem Cell;PAX7: Paired box 7;PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

关键词： Autophagy cancer cachexia Deaf1 FOXO muscle sarcopenia

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