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

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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Polystyrene Nanoplastics Promote Neurodegeneration by Catalyzing Tdp43 Hyperphosphorylation

SSRN

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SSRN 2024年

作者： Ng, Shi-Yan Winanto Tan, Li-Yi Lee, Cheryl Yi-Pin Chooi, Wai Hon Ho, Wan Yun Lim, Yong Shan Soh, Boon Seng Sanford, Emma Tan, Chong-Lun Liou, Yih-Cherng Huang, Cathy Chia-Yu Ling, Shuo-Chien 61 Biopolis Drive Proteos Singapore138673 Singapore National University of Singapore Faculty of Science Department of Biological Science 117543 Singapore National University of Singapore Yong Loo Lin School of Medicine Department of Physiology 117456 Singapore Programs in Neuroscience and Behavioral Disorders Duke-NUS Medical School Singapore Department of Life Sciences National Central University Taoyuan Taiwan Healthy Longevity Translational Research Programme Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore National Neuroscience Institute 308433 Singapore

The ubiquity of polystyrene nanoplastics (PS-NPs) in our environment raises substantial concerns about their potential impact on human health. Recent studies have shown that PS-NPs cross the blood-brain-barrier and accumulate in the central nervous system (CNS), raising the concerns on the causal role of PS-NP exposure and neurodegenerative diseases. In this study, we utilized human-induced pluripotent stem cell-derived neurons to examine the effects of PS-NPs on neuronal function and health. Our results revealed that PS-NPs penetrate neuronal cells in a size-dependent manner, and are bound by various cellular proteins, including TDP43, a key protein implicated in amyotrophic lateral sclerosis (ALS). Interestingly, CK1 and GSK3β kinases that are known to phosphorylate TDP-43 were found to be associated with PS-NPs. This observation suggests that PS-NPs may play a role in facilitating conditions that lead to TDP43 phosphorylation. We further demonstrate that exposure to healthy motor neurons with PS-NPs resulted in ALS-like phenotypes, characterized by hyperphosphorylated TDP-43, disrupted neuronal morphology, impaired mitochondrial respiration, and accelerated motor neuron death. These findings suggest that PS-NPs contribute to the pathogenesis of neurodegenerative diseases such as ALS and highlight the urgent need for strategies to limit human exposure to nanoplastics. © 2024, The Authors. All rights reserved.

关键词： Stem cells

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Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information (vol 91, pg 626, 2022)

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BIOLOGICAL PSYCHIATRY 2022年第7期91卷 690-690页

作者： Maihofer, Adam X. Vinkers, Christiaan H. Department of Psychiatry University of California San Diego La Jolla California Department of Family Medicine and Public Health University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California. Electronic address: amaihofer@health.ucsd.edu. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Psychiatry Massachusetts General Hospital Boston Massachusetts. Social Genetic and Developmental Psychiatry Centre Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom National Institute of Health Research Maudsley Biomedical Research Centre King's College London London United Kingdom. Department of Psychiatry Harvard Medical School Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts Center of Excellence in Depression and Anxiety Disorders Belmont Massachusetts. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts. Department of Psychiatry University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California Research Service Veterans Affairs Healthcare System San Diego California. Duke Molecular Physiology Institute Duke University School of Medicine Durham North Carolina. Department of Psychiatry Veterans Affairs Connecticut Healthcare System West Haven Connecticut Department of Psychiatry Yale University School of Medicine New Haven Connecticut. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Epidemiology Columbia University Mailman School of Public Health New York. Division of Mental Health Atlanta Veterans Affairs Medical Center

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

关键词： GWAS Genetics Heritability PTSD PheWAS Trauma

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Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

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Movement disorders : official journal of the Movement Disorder Society 2023年第2期38卷 286-303页

作者： Eva-Juliane Vollstedt Susen Schaake Katja Lohmann Shalini Padmanabhan Alexis Brice Suzanne Lesage Christelle Tesson Marie Vidailhet Isabel Wurster Faycel Hentati Anat Mirelman Nir Giladi Karen Marder Cheryl Waters Stanley Fahn Meike Kasten Norbert Brüggemann Max Borsche Tatiana Foroud Eduardo Tolosa Alicia Garrido Grazia Annesi Monica Gagliardi Maria Bozi Leonidas Stefanis Joaquim J Ferreira Leonor Correia Guedes Micol Avenali Simona Petrucci Lorraine Clark Ekaterina Y Fedotova Natalya Y Abramycheva Victoria Alvarez Manuel Menéndez-González Silvia Jesús Maestre Pilar Gómez-Garre Pablo Mir Andrea Carmine Belin Caroline Ran Chin-Hsien Lin Ming-Che Kuo David Crosiers Zbigniew K Wszolek Owen A Ross Joseph Jankovic Kenya Nishioka Manabu Funayama Jordi Clarimon Caroline H Williams-Gray Marta Camacho Mario Cornejo-Olivas Luis Torres-Ramirez Yih-Ru Wu Guey-Jen Lee-Chen Ana Morgadinho Teeratorn Pulkes Pichet Termsarasab Daniela Berg Gregor Kuhlenbäumer Andrea A Kühn Friederike Borngräber Giuseppe de Michele Anna De Rosa Alexander Zimprich Andreas Puschmann George D Mellick Jolanta Dorszewska Jonathan Carr Rosangela Ferese Stefano Gambardella Bruce Chase Katerina Markopoulou Wataru Satake Tatsushi Toda Malco Rossi Marcelo Merello Timothy Lynch Diana A Olszewska Shen-Yang Lim Azlina Ahmad-Annuar Ai Huey Tan Bashayer Al-Mubarak Hasmet Hanagasi Dariusz Koziorowski Sibel Ertan Gençer Genç Patricia de Carvalho Aguiar Melinda Barkhuizen Marcia M G Pimentel Rachel Saunders-Pullman Bart van de Warrenburg Susan Bressman Mathias Toft Silke Appel-Cresswell Anthony E Lang Matej Skorvanek Agnita J W Boon Rejko Krüger Esther M Sammler Vitor Tumas Bao-Rong Zhang Gaetan Garraux Sun Ju Chung Yun Joong Kim Juliane Winkelmann Carolyn M Sue Eng-King Tan Joana Damásio Péter Klivényi Vladimir S Kostic David Arkadir Mika Martikainen Vanderci Borges Jens Michael Hertz Laura Brighina Mariana Spitz Oksana Suchowersky Olaf Riess Parimal Das Brit Mollenhauer Emilia M Gatto Maria Skaalum Petersen Nobutaka Hattori Ruey-Meei Wu Sergey N Illarioshkin Enz Institute of Neurogenetics University of Lübeck Lübeck Germany. Research Programs The Michael J. Fox Foundation for Parkinson's Research New York New York USA. Department of Neurology Sorbonne University Paris Brain Institute - ICM Inserm CNRS Assistance Publique Hôpitaux de Paris Pitié-Salpêtrière Hospital Paris France. Sorbonne University Paris Brain Institute - ICM Inserm CNRS Paris France. Department of Neurodegenerative Diseases University of Tuebingen Tuebingen Baden Wuerttemberg Germany Hertie Institute for Clinical Brain Research and German Centre for Neurodegenerative Diseases Tuebingen Germany. Mongi Ben Hmida National Institute of Neurology Tunis Tunisia. Laboratory of Early Markers of Neurodegeneration Neurological Institute Tel-Aviv Medical Center Tel-Aviv Israel Sackler School of Medicine Tel-Aviv University Tel-Aviv Israel Sagol School of Neuroscience Tel-Aviv University Tel-Aviv Israel. Neurological Institute Tel-Aviv Medical Center Tel-Aviv Israel Sackler School of Medicine Sagol School of Neuroscience Tel-Aviv University Tel-Aviv Israel. Department of Neurology Taub Institute for Alzheimer's Disease and the Aging Brain Columbia University New York New York USA. Department of Neurology Columbia University New York New York USA. Department of Psychiatry and Psychotherapy and Institute of Neurogenetics University of Lübeck Lübeck Germany. Department of Neurology and Institute of Neurogenetics University of Lübeck Lübeck Germany. Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA. Parkinson Disease and Movement Disorders Unit Neurology Service Hospital Clínic de Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB) Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona Spain. Institute of Biomedical Research and Innovation National Research Council Cosenza

BACKGROUND:As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE:The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS:We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS:We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS:Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clini

关键词： Parkinson's disease monogenic PD

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Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science : Seattle, WA, USA. 24-26 September 2015

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Implementation science : IS 2016年第1期11 Suppl 1卷 85页

作者： Cara Lewis Doyanne Darnell Suzanne Kerns Maria Monroe-DeVita Sara J. Landes Aaron R. Lyon Cameo Stanick Shannon Dorsey Jill Locke Brigid Marriott Ajeng Puspitasari Caitlin Dorsey Karin Hendricks Andria Pierson Phil Fizur Katherine A. Comtois Lawrence A. Palinkas Patricia Chamberlain Gregory A. Aarons Amy E. Green Mark. G. Ehrhart Elise M. Trott Cathleen E. Willging Maria E. Fernandez Nicholas H. Woolf Shuting Lily Liang Natalia I. Heredia Michelle Kegler Betsy Risendal Andrea Dwyer Vicki Young Dayna Campbell Michelle Carvalho Yvonne Kellar-Guenther Laura J. Damschroder Julie C. Lowery Sarah S. Ono Kathleen F. Carlson Erika K. Cottrell Maya E. O’Neil Travis L. Lovejoy Joanna J. Arch Jill L. Mitchell Cara C. Lewis Brigid R. Marriott Kelli Scott Jennifer Schurer Coldiron Eric J. Bruns Alyssa N. Hook Benjamin C. Graham Katelin Jordan Rochelle F. Hanson Angela Moreland Benjamin E. Saunders Heidi S. Resnick Shannon Wiltsey Stirman Cassidy A. Gutner Jennifer Gamarra Dawne Vogt Michael Suvak Jennifer Schuster Wachen Katherine Dondanville Jeffrey S. Yarvis Jim Mintz Alan L. Peterson Elisa V. Borah Brett T. Litz Alma Molino Stacey Young McCaughan Patricia A. Resick Nancy Pandhi Nora Jacobson Neftali Serrano Armando Hernandez Elizabeth Zeidler- Schreiter Natalie Wietfeldt Zaher Karp Michael D. Pullmann Barbara Lucenko Bridget Pavelle Jacqueline A. Uomoto Andrea Negrete Molly Cevasco Suzanne E. U. Kerns Robert P. Franks Christopher Bory Edward J. Miech Teresa M. Damush Jason Satterfield Derek Satre Maria Wamsley Patrick Yuan Patricia O’Sullivan Helen Best Susan Velasquez Miya Barnett Lauren Brookman-Frazee Jennifer Regan Nicole Stadnick Alison Hamilton Anna Lau Scott Roesch Byron J. Powell Thomas J. Waltz Matthew J. Chinman Laura Damschroder Jeffrey L. Smith Monica M. Matthieu Enola K. Proctor JoAnn E. Kirchner Monica J. Matthieu Craig S. Rosen Sarah C. Walker Asia S. Bishop Mariko Lockhart Allison L. Rodriguez Luisa Manfredi Andrea Nevedal Joel Rosenthal Daniel M. Blonigen Anne M. Mauricio Thomas D. Dishion Jenna Rudo-Stern Department of Psychological and Brain Sciences Indiana University Bloomington USA Department of Psychiatry & Behavioral Sciences University of Washington Seattle USA Psychology Department University of Montana Missoula USA Department of Psychology La Salle University Philadelphia USA Division of Public Behavioral Health and Justice Policy University of Washington Seattle USA National Center for PTSD VA Palo Alto Health Care System Menlo Park USA Department of Psychiatry University of Arkansas for Medical Sciences Little Rock USA Department of Psychology University of Washington Seattle USA Department of Speech and Hearing Sciences University of Washington Seattle USA Department of Psychological Sciences University of Missouri Columbia USA Department of Children Youth and Families School of Social Work University of Southern California Los Angeles USA Oregon Social Learning Center Eugene USA Department of Psychiatry University of California San Diego La Jolla USA Child and Adolescent Services Research Center (CASRC) San Diego USA Department of Psychology San Diego State University San Diego USA Pacific Institute for Research and Evaluation Behavioral Health Research Center of the Southwest Albuquerque USA School of Public Health University of Texas Health Science Center at Houston Houston USA Woolf Consulting Santa Barbara USA Rollins School of Public Health Emory University Atlanta USA University of Colorado Cancer Center at Denver Aurora USA South Carolina Primary Health Care Association Columbia USA Veterans Affairs (VA) Ann Arbor Center for Clinical Management Research Ann Arbor USA Personalizing Options through Veteran Engagement (PROVE) Quality Enhancement Research Initiative (QUERI) Program Ann Arbor USA Center to Improve Veteran Involvement in Care (CIVIC) Veterns Affairs (VA) Portland Health Care System (VAPORHCS) Portland USA Department of Family Medicine Oregon Health & Science University Portland USA Division of General Internal Medi

Introduction to the 3rd Biennial Conference of the Society for Implementation Research Collaboration: advancing efficient methodologies through team science and community partnerships Cara Lewis, Doyanne Darnell, Suzanne Kerns, Maria Monroe-DeVita, Sara J. Landes, Aaron R. Lyon, Cameo Stanick, Shannon Dorsey, Jill Locke, Brigid Marriott, Ajeng Puspitasari, Caitlin Dorsey, Karin Hendricks, Andria Pierson, Phil Fizur, Katherine A. Comtois A1: A behavioral economic perspective on adoption, implementation, and sustainment of evidence-based interventions Lawrence A. Palinkas A2: Towards making scale up of evidence-based practices in child welfare systems more efficient and affordable Patricia Chamberlain A3: Mixed method examination of strategic leadership for evidence-based practice implementation Gregory A. Aarons, Amy E. Green, Mark. G. Ehrhart, Elise M. Trott, Cathleen E. Willging A4: Implementing practice change in Federally Qualified Health Centers: Learning from leaders’ experiences Maria E. Fernandez, Nicholas H. Woolf, Shuting (Lily) Liang, Natalia I. Heredia, Michelle Kegler, Betsy Risendal, Andrea Dwyer, Vicki Young, Dayna Campbell, Michelle Carvalho, Yvonne Kellar-Guenther A3: Mixed method examination of strategic leadership for evidence-based practice implementation Gregory A. Aarons, Amy E. Green, Mark. G. Ehrhart, Elise M. Trott, Cathleen E. Willging A4: Implementing practice change in Federally Qualified Health Centers: Learning from leaders’ experiences Maria E. Fernandez, Nicholas H. Woolf, Shuting (Lily) Liang, Natalia I. Heredia, Michelle Kegler, Betsy Risendal, Andrea Dwyer, Vicki Young, Dayna Campbell, Michelle Carvalho, Yvonne Kellar-Guenther A5: Efficient synthesis: Using qualitative comparative analysis and the Consolidated Framework for Implementation Research across diverse studies Laura J. Damschroder, Julie C. Lowery A6: Establishing a veterans engagement group to empower patients and inform Veterans Affairs (VA) health services research Sara

关键词： Veteran Affair Motivational Interview Veteran Health Administration Dialectical Behavior Therapy Qualitative Comparative Analysis

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Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000-17: analysis for the Global Burden of Disease Study 2017 (vol 395, pg 1779, 2020)

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LANCET 2020年第10239期395卷 1762-1762页

作者： Reiner, R. C., Jr. Hay, S., I Institute for Health Metrics and Evaluation University of Washington Seattle WA United States Department of Global Health School of Medicine University of Washington Seattle WA United States Department of Health Metrics Sciences School of Medicine University of Washington Seattle WA United States College of Health and Medical Sciences Haramaya University Harar Ethiopia Department of Epidemiology and Biostatistics Haramaya University Harar Ethiopia Department of Medical Laboratory Sciences Haramaya University Harar Ethiopia School of Nursing and Midwifery Haramaya University Harar Ethiopia School of Pharmacy Haramaya University Harar Ethiopia School of Public Health Haramaya University Harar Ethiopia Haramaya University Harar Ethiopia Advanced Diagnostic and Interventional Radiology Research Center Tehran University of Medical Sciences Tehran Iran Cancer Biology Research Center Tehran University of Medical Sciences Tehran Iran Cancer Research Institute Tehran University of Medical Sciences Tehran Iran Department of Economics and Management Sciences for Health Tehran University of Medical Sciences Tehran Iran Department of Environmental Health Engineering Tehran University of Medical Sciences Tehran Iran Department of Epidemiology and Biostatistics Tehran University of Medical Sciences Tehran Iran Department of Health Management and Economics Tehran University of Medical Sciences Tehran Iran Department of Microbiology Tehran University of Medical Sciences Tehran Iran Department of Pharmacology Tehran University of Medical Sciences Tehran Iran Digestive Diseases Research Institute Tehran University of Medical Sciences Tehran Iran Endocrinology and Metabolism Research Center Tehran University of Medical Sciences Tehran Iran Hematology-Oncology and Stem Cell Transplantation Research Center Tehran University of Medical Sciences Tehran Iran Iran National Institute of Health Research Tehran University of Medical Sciences Tehran Iran Metabolomics and

Summary Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood *** We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor *** The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1-65·8), 17·4% (7·7-28·4), and 59·5% (34·2-86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy *** By co-analysing geospatial trends in d

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