Pub Date : 2025-11-25DOI: 10.1038/s41593-025-02147-2
Chu-Yi Zhang, Miao Li, Ping Sun, Li Hui, Yuan Gao, Jian-Zhong Yang, Nan Zhang, Xiaoyang Feng, Yong Wu, Lei Guo, Jing Yuan, Hong-Yan Jiang, Yu-Qi Cheng, Simeng Ma, Qian Gong, Yaoyao Sun, Yi Li, Na Qu, Xu-Yuan Yin, Lu Wang, Yongfeng Yang, Chuansheng Wang, Luxian Lv, Dongsheng Zhou, Xingxing Li, Xiaogang Chen, Chen Zhang, Jun Chen, Xueqin Song, Jinsong Tang, Jun Cai, Weixing Fan, Wei Tang, Wenxin Tang, Wenqiang Li, Xia Tang, Xiaoxi Zhang, Yan Lu, Yong-Gang Yao, Chuang Wang, Hon-Cheong So, Nakao Iwata, Masashi Ikeda, Takeo Saito, Zhongchun Liu, Shuahua Xu, Weihua Yue, GeseDNA Research Team, Yiru Fang, Feng Zhu, Xiao Xiao, Ming Li
Genome-wide association studies (GWASs) of bipolar disorder (BD) have predominantly included individuals of European (EUR) ancestry, underrepresenting non-EUR populations and limiting insight into disease mechanisms. Here we performed a GWAS of BD in Han Chinese individuals (5,164 cases and 13,460 controls) and conducted comparative and integrative analyses with independent East Asian (EAS, 4,479 cases and 75,725 controls) and EUR (59,287 cases and 781,022 controls) cohorts from the PGC4 GWAS. Our GWAS in EAS ancestry identified two genome-wide significant risk loci, including variants at the major histocompatibility complex (MHC) class II region. Incorporating EAS data into trans-ancestry GWAS revealed 93 significant loci (23 novel). Heritability enrichment analyses implicated a variety of neuronal cell types. Multidimensional post-GWAS prioritization identified 39 high-confidence risk genes, of which 15 were differentially expressed in the brains of patients with BD, 12 modulated BD-relevant behaviors in mice and 18 are pharmacologically tractable. This work advances understanding of the biological underpinnings of BD and provides direction for future research in underrepresented populations. The authors conducted a genome-wide association study of bipolar disorder (BD) in Han Chinese and integrated PGC4 East Asian and European datasets, discovering 23 novel loci, prioritizing 39 credible risk genes and implicating BD-related cell types and druggable targets.
{"title":"Trans-ancestry genome-wide analyses of bipolar disorder in East Asian and European populations improve genetic discovery","authors":"Chu-Yi Zhang, Miao Li, Ping Sun, Li Hui, Yuan Gao, Jian-Zhong Yang, Nan Zhang, Xiaoyang Feng, Yong Wu, Lei Guo, Jing Yuan, Hong-Yan Jiang, Yu-Qi Cheng, Simeng Ma, Qian Gong, Yaoyao Sun, Yi Li, Na Qu, Xu-Yuan Yin, Lu Wang, Yongfeng Yang, Chuansheng Wang, Luxian Lv, Dongsheng Zhou, Xingxing Li, Xiaogang Chen, Chen Zhang, Jun Chen, Xueqin Song, Jinsong Tang, Jun Cai, Weixing Fan, Wei Tang, Wenxin Tang, Wenqiang Li, Xia Tang, Xiaoxi Zhang, Yan Lu, Yong-Gang Yao, Chuang Wang, Hon-Cheong So, Nakao Iwata, Masashi Ikeda, Takeo Saito, Zhongchun Liu, Shuahua Xu, Weihua Yue, GeseDNA Research Team, Yiru Fang, Feng Zhu, Xiao Xiao, Ming Li","doi":"10.1038/s41593-025-02147-2","DOIUrl":"10.1038/s41593-025-02147-2","url":null,"abstract":"Genome-wide association studies (GWASs) of bipolar disorder (BD) have predominantly included individuals of European (EUR) ancestry, underrepresenting non-EUR populations and limiting insight into disease mechanisms. Here we performed a GWAS of BD in Han Chinese individuals (5,164 cases and 13,460 controls) and conducted comparative and integrative analyses with independent East Asian (EAS, 4,479 cases and 75,725 controls) and EUR (59,287 cases and 781,022 controls) cohorts from the PGC4 GWAS. Our GWAS in EAS ancestry identified two genome-wide significant risk loci, including variants at the major histocompatibility complex (MHC) class II region. Incorporating EAS data into trans-ancestry GWAS revealed 93 significant loci (23 novel). Heritability enrichment analyses implicated a variety of neuronal cell types. Multidimensional post-GWAS prioritization identified 39 high-confidence risk genes, of which 15 were differentially expressed in the brains of patients with BD, 12 modulated BD-relevant behaviors in mice and 18 are pharmacologically tractable. This work advances understanding of the biological underpinnings of BD and provides direction for future research in underrepresented populations. The authors conducted a genome-wide association study of bipolar disorder (BD) in Han Chinese and integrated PGC4 East Asian and European datasets, discovering 23 novel loci, prioritizing 39 credible risk genes and implicating BD-related cell types and druggable targets.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"293-305"},"PeriodicalIF":20.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1038/s41593-025-02086-y
Gonadal hormones shape brain structure across the lifespan. Using dense sampling in two female participants with typical cycles, one with endometriosis, and one using oral contraceptives, we show that distinct hormonal milieus influence widespread, coordinated fluctuations in brain volume across the cycle. These results highlight the importance of looking beyond the ‘typical’ menstrual cycle to understand how hormones drive structural brain plasticity in different conditions.
{"title":"Estrogen dominance drives distinct patterns of brain plasticity","authors":"","doi":"10.1038/s41593-025-02086-y","DOIUrl":"10.1038/s41593-025-02086-y","url":null,"abstract":"Gonadal hormones shape brain structure across the lifespan. Using dense sampling in two female participants with typical cycles, one with endometriosis, and one using oral contraceptives, we show that distinct hormonal milieus influence widespread, coordinated fluctuations in brain volume across the cycle. These results highlight the importance of looking beyond the ‘typical’ menstrual cycle to understand how hormones drive structural brain plasticity in different conditions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2413-2414"},"PeriodicalIF":20.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1038/s41593-025-02163-2
Carina Heller, Daniel Güllmar, Lejla Colic, Laura Pritschet, Martin Gell, Nooshin Javaheripour, Feliberto de la Cruz, Philine Rojczyk, Carina J. Koeppel, Bart Larsen, Habib Ganjgahi, Frederik J. Lange, Ann-Christine Buck, Tim L. Jesgarzewsky, Robert Dahnke, Michael Kiehntopf, Emily G. Jacobs, Zora Kikinis, Martin Walter, Ilona Croy, Christian Gaser
{"title":"Publisher Correction: Hormonal milieu influences whole-brain structural dynamics across the menstrual cycle using dense sampling in multiple individuals","authors":"Carina Heller, Daniel Güllmar, Lejla Colic, Laura Pritschet, Martin Gell, Nooshin Javaheripour, Feliberto de la Cruz, Philine Rojczyk, Carina J. Koeppel, Bart Larsen, Habib Ganjgahi, Frederik J. Lange, Ann-Christine Buck, Tim L. Jesgarzewsky, Robert Dahnke, Michael Kiehntopf, Emily G. Jacobs, Zora Kikinis, Martin Walter, Ilona Croy, Christian Gaser","doi":"10.1038/s41593-025-02163-2","DOIUrl":"10.1038/s41593-025-02163-2","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2647-2647"},"PeriodicalIF":20.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02163-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02111-0
Tjitse van der Molen, Alex Spaeth, Mattia Chini, Sebastian Hernandez, Gregory A. Kaurala, Hunter E. Schweiger, Cole Duncan, Sawyer McKenna, Jinghui Geng, Max Lim, Julian Bartram, Tobias Gänswein, Aditya Dendukuri, Zongren Zhang, Jesus Gonzalez-Ferrer, Kiran Bhaskaran-Nair, Aidan L. Morson, Cole R. K. Harder, Linda R. Petzold, Dowlette-Mary Alam El Din, Jason Laird, Maren Schenke, Lena Smirnova, Bradley M. Colquitt, Mohammed A. Mostajo-Radji, Paul K. Hansma, Mircea Teodorescu, Andreas Hierlemann, Keith B. Hengen, Ileana L. Hanganu-Opatz, Kenneth S. Kosik, Tal Sharf
Neuronal firing sequences are thought to be the building blocks of information and broadcasting within the brain. Yet, it remains unclear when these sequences emerge during neurodevelopment. Here we demonstrate that structured firing sequences appear in spontaneous activity of human and murine brain organoids, both unguided and forebrain identity directed, as well as ex vivo neonatal murine cortical slices. We observed temporally rigid and flexible firing patterns in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in dissociated primary cortical cultures. These results suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by a preconfigured architecture established during neurodevelopment. By demonstrating the developmental recapitulation of neural firing patterns, these findings highlight the potential of brain organoids as a model for neuronal circuit assembly. Examining human brain organoids and ex vivo neonatal murine cortical slices demonstrates that structured neuronal sequences emerge independently of sensory input, highlighting the potential of brain organoids as a model for neuronal circuit assembly.
{"title":"Preconfigured neuronal firing sequences in human brain organoids","authors":"Tjitse van der Molen, Alex Spaeth, Mattia Chini, Sebastian Hernandez, Gregory A. Kaurala, Hunter E. Schweiger, Cole Duncan, Sawyer McKenna, Jinghui Geng, Max Lim, Julian Bartram, Tobias Gänswein, Aditya Dendukuri, Zongren Zhang, Jesus Gonzalez-Ferrer, Kiran Bhaskaran-Nair, Aidan L. Morson, Cole R. K. Harder, Linda R. Petzold, Dowlette-Mary Alam El Din, Jason Laird, Maren Schenke, Lena Smirnova, Bradley M. Colquitt, Mohammed A. Mostajo-Radji, Paul K. Hansma, Mircea Teodorescu, Andreas Hierlemann, Keith B. Hengen, Ileana L. Hanganu-Opatz, Kenneth S. Kosik, Tal Sharf","doi":"10.1038/s41593-025-02111-0","DOIUrl":"10.1038/s41593-025-02111-0","url":null,"abstract":"Neuronal firing sequences are thought to be the building blocks of information and broadcasting within the brain. Yet, it remains unclear when these sequences emerge during neurodevelopment. Here we demonstrate that structured firing sequences appear in spontaneous activity of human and murine brain organoids, both unguided and forebrain identity directed, as well as ex vivo neonatal murine cortical slices. We observed temporally rigid and flexible firing patterns in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in dissociated primary cortical cultures. These results suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by a preconfigured architecture established during neurodevelopment. By demonstrating the developmental recapitulation of neural firing patterns, these findings highlight the potential of brain organoids as a model for neuronal circuit assembly. Examining human brain organoids and ex vivo neonatal murine cortical slices demonstrates that structured neuronal sequences emerge independently of sensory input, highlighting the potential of brain organoids as a model for neuronal circuit assembly.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"123-135"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02117-8
Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Haipeng Xue, Jesse Pascual, Hanwen Yu, Ava V. Papetti, Yan Liu, Steven Finkbeiner, Elizabeth Head, Ying Liu, Peng Jiang
Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies. Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.
{"title":"A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease","authors":"Mengmeng Jin, Ziyuan Ma, Rui Dang, Haiwei Zhang, Rachael Kim, Haipeng Xue, Jesse Pascual, Hanwen Yu, Ava V. Papetti, Yan Liu, Steven Finkbeiner, Elizabeth Head, Ying Liu, Peng Jiang","doi":"10.1038/s41593-025-02117-8","DOIUrl":"10.1038/s41593-025-02117-8","url":null,"abstract":"Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence. CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies. Engineering human microglia with a Down-syndrome-linked myeloid gene variant resists tau-induced dysfunction and protects neurons in chimeric brains, offering proof of concept for transformative microglial replacement therapies in Alzheimer’s disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"25-39"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02125-8
Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper
Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease. Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.
{"title":"The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia","authors":"Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper","doi":"10.1038/s41593-025-02125-8","DOIUrl":"10.1038/s41593-025-02125-8","url":null,"abstract":"Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease. Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"100-110"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02125-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02118-7
Christopher R. Bye, Elizabeth Qian, Katherine Lim, Maciej Daniszewski, Fleur C. Garton, Bảo C. Trần-Lê, Helena H. Liang, Tian Lin, John G. Lock, Duncan E. Crombie, Steven Morgan, Yi Hu, Samantha K. Barton, Lucy M. Palmer, Elvan Djouma, Saritha Kodikara, Kim-Anh Lê Cao, Thanuja Dharmadasa, Anjali K. Henders, Laura A. Ziser, Matthew C. Kiernan, Kevin Talbot, Merrilee Needham, Susan Fletcher, Paul Talman, Susan Mathers, Naomi R. Wray, Alex W. Hewitt, Alice Pebay, Bradley J. Turner
Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS. In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.
{"title":"Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy","authors":"Christopher R. Bye, Elizabeth Qian, Katherine Lim, Maciej Daniszewski, Fleur C. Garton, Bảo C. Trần-Lê, Helena H. Liang, Tian Lin, John G. Lock, Duncan E. Crombie, Steven Morgan, Yi Hu, Samantha K. Barton, Lucy M. Palmer, Elvan Djouma, Saritha Kodikara, Kim-Anh Lê Cao, Thanuja Dharmadasa, Anjali K. Henders, Laura A. Ziser, Matthew C. Kiernan, Kevin Talbot, Merrilee Needham, Susan Fletcher, Paul Talman, Susan Mathers, Naomi R. Wray, Alex W. Hewitt, Alice Pebay, Bradley J. Turner","doi":"10.1038/s41593-025-02118-7","DOIUrl":"10.1038/s41593-025-02118-7","url":null,"abstract":"Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS. In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"40-52"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02118-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain atlases map the spatial organization of neural tissue and serve as anatomical references. Current mouse brain atlases define regions based primarily on cell density patterns but overlook how neurons extend their branches (dendrites) to form local networks. Here we show that mapping dendrites enhanced by their local neighborhoods—which we call microenvironments—reveals a finer-grained brain organization. We analyzed dendrite patterns from more than 100,000 neurons across 111 mouse brains and discovered that neurons group into distinct microenvironments that subdivide known brain regions, nearly doubling the number of identifiable areas compared with the standard Allen Common Coordinate Framework. Remarkably, hippocampal neurons with similar local dendrite arrangements tend to form long-range connections to similar distant targets, suggesting that local structure predicts global connectivity. This microenvironment atlas complements existing resources by revealing previously hidden subdivisions and correlations that align with functional differences, offering new insights into how brain structure relates to function. The authors developed a mouse brain atlas using local dendritic morphological patterns from 101,136 neurons. This representation not only improves anatomical precision but also uncovers associations between local dendritic architecture and long-range neuronal projections.
{"title":"A mouse brain atlas based on dendritic microenvironments","authors":"Yufeng Liu, Sujun Zhao, Zhixi Yun, Feng Xiong, Hanchuan Peng","doi":"10.1038/s41593-025-02119-6","DOIUrl":"10.1038/s41593-025-02119-6","url":null,"abstract":"Brain atlases map the spatial organization of neural tissue and serve as anatomical references. Current mouse brain atlases define regions based primarily on cell density patterns but overlook how neurons extend their branches (dendrites) to form local networks. Here we show that mapping dendrites enhanced by their local neighborhoods—which we call microenvironments—reveals a finer-grained brain organization. We analyzed dendrite patterns from more than 100,000 neurons across 111 mouse brains and discovered that neurons group into distinct microenvironments that subdivide known brain regions, nearly doubling the number of identifiable areas compared with the standard Allen Common Coordinate Framework. Remarkably, hippocampal neurons with similar local dendrite arrangements tend to form long-range connections to similar distant targets, suggesting that local structure predicts global connectivity. This microenvironment atlas complements existing resources by revealing previously hidden subdivisions and correlations that align with functional differences, offering new insights into how brain structure relates to function. The authors developed a mouse brain atlas using local dendritic morphological patterns from 101,136 neurons. This representation not only improves anatomical precision but also uncovers associations between local dendritic architecture and long-range neuronal projections.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"111-122"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02119-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41593-025-02140-9
Qing Pei, Qixin Chen, Zhiqi Tian, Le Zhu, Yang Chen, Jihong Gong, Shen Wang, Yijuan Xiang, John S. Khamo, Jiaqi Fan, Yi Rong, Yi Yu, Yuyang Qin, Shiping Wu, Youssef Faragalla, Peng Cao, Kai Zhang, Ying Lai, Ling-Gang Wu, Cong Ma, Xiaofei Yang, Jiajie Diao
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion. Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.
{"title":"Munc18 modulates syntaxin phase separation to promote exocytosis","authors":"Qing Pei, Qixin Chen, Zhiqi Tian, Le Zhu, Yang Chen, Jihong Gong, Shen Wang, Yijuan Xiang, John S. Khamo, Jiaqi Fan, Yi Rong, Yi Yu, Yuyang Qin, Shiping Wu, Youssef Faragalla, Peng Cao, Kai Zhang, Ying Lai, Ling-Gang Wu, Cong Ma, Xiaofei Yang, Jiajie Diao","doi":"10.1038/s41593-025-02140-9","DOIUrl":"10.1038/s41593-025-02140-9","url":null,"abstract":"The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion. Syntaxin-1A, a SNARE protein mediating membrane fusion for neurotransmission, forms clusters with unclear functions. Using light-controlled clustering, the authors found that phase-separation-driven clusters, regulated by Munc18, suppress fusion, revealing a new phase-separation-based mechanism.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"306-314"},"PeriodicalIF":20.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1038/s41593-025-02115-w
Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen
Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer’s disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9−MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Astrocytes are associated with Alzheimer’s disease pathogenesis. We found that the transcription factor Sox9 functions to enhance astrocytic phagocytosis of Aβ plaques via MEGF10, and this clearance of plaques is associated with the preservation of cognitive function in mouse models.
{"title":"Astrocytic Sox9 overexpression in Alzheimer’s disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function","authors":"Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen","doi":"10.1038/s41593-025-02115-w","DOIUrl":"10.1038/s41593-025-02115-w","url":null,"abstract":"Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer’s disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9−MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Astrocytes are associated with Alzheimer’s disease pathogenesis. We found that the transcription factor Sox9 functions to enhance astrocytic phagocytosis of Aβ plaques via MEGF10, and this clearance of plaques is associated with the preservation of cognitive function in mouse models.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"88-99"},"PeriodicalIF":20.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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