Nature neuroscience最新文献_第8页

TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model TYK2 在牛磺酸病小鼠模型中调控牛磺酸水平、磷酸化和聚集

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-11 DOI: 10.1038/s41593-024-01777-2

Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-eun Chloe Chung, Bradley Hyman, David M. Holtzman, Huda Yahya Zoghbi

{"title":"TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model","authors":"Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-eun Chloe Chung, Bradley Hyman, David M. Holtzman, Huda Yahya Zoghbi","doi":"10.1038/s41593-024-01777-2","DOIUrl":"10.1038/s41593-024-01777-2","url":null,"abstract":"Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity. Tyrosine kinase 2 (TYK2) critically regulates tau levels and aggregation by phosphorylating tau’s tyrosine 29. Partial inhibition of TYK2 mitigates tau pathologies in cells and mice, highlighting TYK2 as a potential therapeutic target for Alzheimer’s disease and other tauopathies.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2417-2429"},"PeriodicalIF":21.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01777-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597969","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}

引用次数: 0

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease 星形胶质细胞转录组在阿尔茨海默病时空进展过程中的变化

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-11 DOI: 10.1038/s41593-024-01791-4

Alberto Serrano-Pozo, Huan Li, Zhaozhi Li, Clara Muñoz-Castro, Methasit Jaisa-aad, Molly A. Healey, Lindsay A. Welikovitch, Rojashree Jayakumar, Annie G. Bryant, Ayush Noori, Theresa R. Connors, Miwei Hu, Karen Zhao, Fan Liao, Gen Lin, Timothy Pastika, Joseph Tamm, Aicha Abdourahman, Taekyung Kwon, Rachel E. Bennett, Maya E. Woodbury, Astrid Wachter, Robert V. Talanian, Knut Biber, Eric H. Karran, Bradley T. Hyman, Sudeshna Das

{"title":"Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease","authors":"Alberto Serrano-Pozo, Huan Li, Zhaozhi Li, Clara Muñoz-Castro, Methasit Jaisa-aad, Molly A. Healey, Lindsay A. Welikovitch, Rojashree Jayakumar, Annie G. Bryant, Ayush Noori, Theresa R. Connors, Miwei Hu, Karen Zhao, Fan Liao, Gen Lin, Timothy Pastika, Joseph Tamm, Aicha Abdourahman, Taekyung Kwon, Rachel E. Bennett, Maya E. Woodbury, Astrid Wachter, Robert V. Talanian, Knut Biber, Eric H. Karran, Bradley T. Hyman, Sudeshna Das","doi":"10.1038/s41593-024-01791-4","DOIUrl":"10.1038/s41593-024-01791-4","url":null,"abstract":"Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD. Using single-nucleus RNA sequencing from 32 donors, researchers identified distinct astrocytic gene expression programs activated across brain regions and Alzheimer’s disease stages. They also found unique subclusters of astrocytes that appear to vary over time, highlighting the complexity of astrocytic responses in AD.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2384-2400"},"PeriodicalIF":21.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01791-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597925","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}

引用次数: 0

Deep RNA sequencing of human dorsal root ganglion neurons reveals somatosensory mechanisms 人类背根神经节神经元的深度 RNA 测序揭示了躯体感觉机制

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-06 DOI: 10.1038/s41593-024-01795-0

引用次数: 0

Mapping out multiple sclerosis with spatial transcriptomics 利用空间转录组学绘制多发性硬化症地图

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-05 DOI: 10.1038/s41593-024-01798-x

Kellie Horan, Anna C. Williams

引用次数: 0

Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis 多发性硬化症白质病变进展的空间分辨基因特征

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-05 DOI: 10.1038/s41593-024-01765-6

Astrid M. Alsema, Marion H. C. Wijering, Anneke Miedema, Janssen M. Kotah, Mirjam Koster, Merel Rijnsburger, Hilmar R. J. van Weering, Helga E. de Vries, Wia Baron, Susanne M. Kooistra, Bart J. L. Eggen

{"title":"Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis","authors":"Astrid M. Alsema, Marion H. C. Wijering, Anneke Miedema, Janssen M. Kotah, Mirjam Koster, Merel Rijnsburger, Hilmar R. J. van Weering, Helga E. de Vries, Wia Baron, Susanne M. Kooistra, Bart J. L. Eggen","doi":"10.1038/s41593-024-01765-6","DOIUrl":"10.1038/s41593-024-01765-6","url":null,"abstract":"Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and progressive neurodegeneration. To understand MS lesion initiation and progression, we generate spatial gene expression maps of white matter (WM) and grey matter (GM) MS lesions. In different MS lesion types, we detect domains characterized by a distinct gene signature, including an identifiable rim around active WM lesions. Expression changes in astrocyte-specific, oligodendrocyte-specific and microglia-specific gene sets characterize the active lesion rims. Furthermore, we identify three WM lesion progression trajectories, predicting how normal-appearing WM can develop into WM active or mixed active–inactive lesions. Our data shed light on the dynamic progression of MS lesions. Lesion initiation and progression in multiple sclerosis is a dynamic but unclear process. Here, the authors highlight cell type-specific gene sets characterizing the action lesion rims and identify trajectories, predicting how normal-appearing white matter can develop into active and mixed active/inactive lesions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2341-2353"},"PeriodicalIF":21.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580337","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}

引用次数: 0

Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions 细胞类型图揭示皮层下多发性硬化病变中的组织龛位和相互作用

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-05 DOI: 10.1038/s41593-024-01796-z

Celia Lerma-Martin, Pau Badia-i-Mompel, Ricardo O. Ramirez Flores, Patricia Sekol, Philipp S. L. Schäfer, Christian J. Riedl, Annika Hofmann, Thomas Thäwel, Florian Wünnemann, Miguel A. Ibarra-Arellano, Tim Trobisch, Philipp Eisele, Denis Schapiro, Maximilian Haeussler, Simon Hametner, Julio Saez-Rodriguez, Lucas Schirmer

{"title":"Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions","authors":"Celia Lerma-Martin, Pau Badia-i-Mompel, Ricardo O. Ramirez Flores, Patricia Sekol, Philipp S. L. Schäfer, Christian J. Riedl, Annika Hofmann, Thomas Thäwel, Florian Wünnemann, Miguel A. Ibarra-Arellano, Tim Trobisch, Philipp Eisele, Denis Schapiro, Maximilian Haeussler, Simon Hametner, Julio Saez-Rodriguez, Lucas Schirmer","doi":"10.1038/s41593-024-01796-z","DOIUrl":"10.1038/s41593-024-01796-z","url":null,"abstract":"Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation is gradually compartmentalized and restricted to specific tissue niches such as the lesion rim. However, the precise cell type composition of such niches, their interactions and changes between chronic active and inactive stages are incompletely understood. We used single-nucleus and spatial transcriptomics from subcortical MS and corresponding control tissues to map cell types and associated pathways to lesion and nonlesion areas. We identified niches such as perivascular spaces, the inflamed lesion rim or the lesion core that are associated with the glial scar and a cilia-forming astrocyte subtype. Focusing on the inflamed rim of chronic active lesions, we uncovered cell–cell communication events between myeloid, endothelial and glial cell types. Our results provide insight into the cellular composition, multicellular programs and intercellular communication in tissue niches along the conversion from a homeostatic to a dysfunctional state underlying lesion progression in MS. Lerma-Martin et al. generated a paired single-nucleus RNA sequencing and spatial transcriptomics dataset from subcortical multiple sclerosis lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2354-2365"},"PeriodicalIF":21.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01796-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580336","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}

引用次数: 0

Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation 利用深度单瘤 RNA 测序探索人类躯体感觉的神经基础

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-04 DOI: 10.1038/s41593-024-01794-1

Huasheng Yu, Saad S. Nagi, Dmitry Usoskin, Yizhou Hu, Jussi Kupari, Otmane Bouchatta, Hanying Yan, Suna Li Cranfill, Mayank Gautam, Yijing Su, You Lu, James Wymer, Max Glanz, Phillip Albrecht, Hongjun Song, Guo-Li Ming, Stephen Prouty, John Seykora, Hao Wu, Minghong Ma, Andrew Marshall, Frank L. Rice, Mingyao Li, Håkan Olausson, Patrik Ernfors, Wenqin Luo

{"title":"Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation","authors":"Huasheng Yu, Saad S. Nagi, Dmitry Usoskin, Yizhou Hu, Jussi Kupari, Otmane Bouchatta, Hanying Yan, Suna Li Cranfill, Mayank Gautam, Yijing Su, You Lu, James Wymer, Max Glanz, Phillip Albrecht, Hongjun Song, Guo-Li Ming, Stephen Prouty, John Seykora, Hao Wu, Minghong Ma, Andrew Marshall, Frank L. Rice, Mingyao Li, Håkan Olausson, Patrik Ernfors, Wenqin Luo","doi":"10.1038/s41593-024-01794-1","DOIUrl":"10.1038/s41593-024-01794-1","url":null,"abstract":"The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human (h)DRG neurons—critical information to decipher their functions—are lacking due to technical difficulties. In this study, we isolated somata from individual hDRG neurons and conducted deep RNA sequencing (RNA-seq) to detect, on average, over 9,000 unique genes per neuron, and we identified 16 neuronal types. These results were corroborated and validated by spatial transcriptomics and RNAscope in situ hybridization. Cross-species analyses revealed divergence among potential pain-sensing neurons and the likely existence of human-specific neuronal types. Molecular-profile-informed microneurography recordings revealed temperature-sensing properties across human sensory afferent types. In summary, by employing single-soma deep RNA-seq and spatial transcriptomics, we generated an hDRG neuron atlas, which provides insights into human somatosensory physiology and serves as a foundation for translational work. Dorsal root ganglia (DRGs) contain a plethora of neuron types. The authors show that the existence of human-specific DRG neuronal types and microneurography recordings reveal distinct temperature-sensing properties across human sensory afferent types.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2326-2340"},"PeriodicalIF":21.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01794-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574473","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}

引用次数: 0

The role of motor cortex in motor sequence execution depends on demands for flexibility 运动皮层在运动序列执行中的作用取决于对灵活性的要求

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-04 DOI: 10.1038/s41593-024-01792-3

Kevin G. C. Mizes, Jack Lindsey, G. Sean Escola, Bence P. Ölveczky

{"title":"The role of motor cortex in motor sequence execution depends on demands for flexibility","authors":"Kevin G. C. Mizes, Jack Lindsey, G. Sean Escola, Bence P. Ölveczky","doi":"10.1038/s41593-024-01792-3","DOIUrl":"10.1038/s41593-024-01792-3","url":null,"abstract":"The role of the motor cortex in executing motor sequences is widely debated, with studies supporting disparate views. Here we probe the degree to which the motor cortex’s engagement depends on task demands, specifically whether its role differs for highly practiced, or ‘automatic’, sequences versus flexible sequences informed by external cues. To test this, we trained rats to generate three-element motor sequences either by overtraining them on a single sequence or by having them follow instructive visual cues. Lesioning motor cortex showed that it is necessary for flexible cue-driven motor sequences but dispensable for single automatic behaviors trained in isolation. However, when an automatic motor sequence was practiced alongside the flexible task, it became motor cortex dependent, suggesting that an automatic motor sequence fails to consolidate subcortically when the same sequence is produced also in a flexible context. A simple neural network model recapitulated these results and offered a circuit-level explanation. Our results critically delineate the role of the motor cortex in motor sequence execution, describing the conditions under which it is engaged and the functions it fulfills, thus reconciling seemingly conflicting views about motor cortex’s role in motor sequence generation. Motor cortex is required for flexible motor sequences informed by sensory cues but not for single automatic sequences. However, training automatic sequences alongside flexible ones interferes with their subcortical consolidation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2466-2475"},"PeriodicalIF":21.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574472","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}

引用次数: 0

Alcohol’s necessary accessory 酒精的必需品

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-04 DOI: 10.1038/s41593-024-01802-4

Shari Wiseman

引用次数: 0

The fly’s neural blueprint 苍蝇的神经蓝图

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-11-04 DOI: 10.1038/s41593-024-01804-2

Henrietta Howells

引用次数: 0