Felipe Correa-da-Silva, Jenny Carter, Xin-Yuan Wang, Rui Sun, Ekta Pathak, José Manuel Monroy Kuhn, Sonja C Schriever, Clarissa M Maya-Monteiro, Han Jiao, Martin J Kalsbeek, Pedro M M Moraes-Vieira, Johan J P Gille, Margje Sinnema, Constance T R M Stumpel, Leopold M G Curfs, Dirk Jan Stenvers, Paul T Pfluger, Dominik Lutter, Alberto M Pereira, Andries Kalsbeek, Eric Fliers, Dick F Swaab, Lawrence Wilkinson, Yuanqing Gao, Chun-Xia Yi
{"title":"小胶质细胞吞噬小体功能障碍和神经通信改变扩大了普拉德-威利综合征大缺失的表型严重性。","authors":"Felipe Correa-da-Silva, Jenny Carter, Xin-Yuan Wang, Rui Sun, Ekta Pathak, José Manuel Monroy Kuhn, Sonja C Schriever, Clarissa M Maya-Monteiro, Han Jiao, Martin J Kalsbeek, Pedro M M Moraes-Vieira, Johan J P Gille, Margje Sinnema, Constance T R M Stumpel, Leopold M G Curfs, Dirk Jan Stenvers, Paul T Pfluger, Dominik Lutter, Alberto M Pereira, Andries Kalsbeek, Eric Fliers, Dick F Swaab, Lawrence Wilkinson, Yuanqing Gao, Chun-Xia Yi","doi":"10.1007/s00401-024-02714-0","DOIUrl":null,"url":null,"abstract":"<p><p>Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10982101/pdf/","citationCount":"0","resultStr":"{\"title\":\"Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.\",\"authors\":\"Felipe Correa-da-Silva, Jenny Carter, Xin-Yuan Wang, Rui Sun, Ekta Pathak, José Manuel Monroy Kuhn, Sonja C Schriever, Clarissa M Maya-Monteiro, Han Jiao, Martin J Kalsbeek, Pedro M M Moraes-Vieira, Johan J P Gille, Margje Sinnema, Constance T R M Stumpel, Leopold M G Curfs, Dirk Jan Stenvers, Paul T Pfluger, Dominik Lutter, Alberto M Pereira, Andries Kalsbeek, Eric Fliers, Dick F Swaab, Lawrence Wilkinson, Yuanqing Gao, Chun-Xia Yi\",\"doi\":\"10.1007/s00401-024-02714-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.</p>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2024-03-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10982101/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00401-024-02714-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00401-024-02714-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.