IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 Epub Date: 2024-10-14 DOI: 10.1016/j.neuron.2024.08.021

Baptiste Libé-Philippot, Ryohei Iwata, Aleksandra J Recupero, Keimpe Wierda, Sergio Bernal Garcia, Luke Hammond, Anja van Benthem, Ridha Limame, Martyna Ditkowska, Sofie Beckers, Vaiva Gaspariunaite, Eugénie Peze-Heidsieck, Daan Remans, Cécile Charrier, Tom Theys, Franck Polleux, Pierre Vanderhaeghen

{"title":"Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.","authors":"Baptiste Libé-Philippot, Ryohei Iwata, Aleksandra J Recupero, Keimpe Wierda, Sergio Bernal Garcia, Luke Hammond, Anja van Benthem, Ridha Limame, Martyna Ditkowska, Sofie Beckers, Vaiva Gaspariunaite, Eugénie Peze-Heidsieck, Daan Remans, Cécile Charrier, Tom Theys, Franck Polleux, Pierre Vanderhaeghen","doi":"10.1016/j.neuron.2024.08.021","DOIUrl":"10.1016/j.neuron.2024.08.021","url":null,"abstract":"Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3602-3617.e9"},"PeriodicalIF":14.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11546603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471085","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

Gastrointestinal tract cleavage of α-synuclein by asparaginyl endopeptidase leads to Parkinson's disease. 天冬酰胺酰内肽酶通过胃肠道裂解α-突触核蛋白导致帕金森病。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 DOI: 10.1016/j.neuron.2024.10.015

Longfei Li, Valina L Dawson, Ted M Dawson

引用次数: 0

Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk. 基因共表达的全网络风险趋同确定了精神分裂症风险的可重现遗传中心。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 Epub Date: 2024-09-04 DOI: 10.1016/j.neuron.2024.08.005

Christopher Borcuk, Madhur Parihar, Leonardo Sportelli, Joel E Kleinman, Joo Heon Shin, Thomas M Hyde, Alessandro Bertolino, Daniel R Weinberger, Giulio Pergola

{"title":"Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk.","authors":"Christopher Borcuk, Madhur Parihar, Leonardo Sportelli, Joel E Kleinman, Joo Heon Shin, Thomas M Hyde, Alessandro Bertolino, Daniel R Weinberger, Giulio Pergola","doi":"10.1016/j.neuron.2024.08.005","DOIUrl":"10.1016/j.neuron.2024.08.005","url":null,"abstract":"The omnigenic model posits that genetic risk for traits with complex heritability involves cumulative effects of peripheral genes on mechanistic \"core genes,\" suggesting that in a network of genes, those closer to clusters including core genes should have higher GWAS signals. In gene co-expression networks, we confirmed that GWAS signals accumulate in genes more connected to risk-enriched gene clusters, highlighting across-network risk convergence. This was strongest in adult psychiatric disorders, especially schizophrenia (SCZ), spanning 70% of network genes, suggestive of super-polygenic architecture. In snRNA-seq cell type networks, SCZ risk convergence was strongest in L2/L3 excitatory neurons. We prioritized genes most connected to SCZ-GWAS genes, which showed robust association to a CRISPRa measure of PGC3 regulation and were consistently identified across several brain regions. Several genes, including dopamine-associated ones, were prioritized specifically in the striatum. This strategy thus retrieves current drug targets and can be used to prioritize other potential drug targets.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3551-3566.e6"},"PeriodicalIF":14.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140674","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

Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence. 胶质母细胞瘤功能异质性和肿瘤干细胞富集与肿瘤复发的关系

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 DOI: 10.1016/j.neuron.2024.10.012

Xuanhua P Xie, Mungunsarnai Ganbold, Jing Li, Michelle Lien, Mollie E Chipman, Tao Wang, Chenura D Jayewickreme, Alicia M Pedraza, Tejus Bale, Viviane Tabar, Cameron Brennan, Daochun Sun, Roshan Sharma, Luis F Parada

{"title":"Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.","authors":"Xuanhua P Xie, Mungunsarnai Ganbold, Jing Li, Michelle Lien, Mollie E Chipman, Tao Wang, Chenura D Jayewickreme, Alicia M Pedraza, Tejus Bale, Viviane Tabar, Cameron Brennan, Daochun Sun, Roshan Sharma, Luis F Parada","doi":"10.1016/j.neuron.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.neuron.2024.10.012","url":null,"abstract":"Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs). Unsupervised single-cell transcriptomic analysis of patient-derived xenografts (PDXs) delineates six GBM transcriptional states with unique tumor exclusive gene signatures, five of which display congruence with central nervous system (CNS) cell lineages. We employ a surrogate tumor evolution assay by serial xenograft transplantation to demonstrate faithful preservation of somatic mutations, transcriptome, and qCSCs. PDX chemotherapy results in CSC resistance and expansion, also seen in recurrent patient GBM. In aggregate, these novel GBM transcriptional signatures exclusively identify tumor cells and define the hierarchical landscape as stable biologically discernible cell types that allow capture of their evolution upon recurrence, emphasizing the importance of CSCs and demonstrating general relevance to all GBM.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604601","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

Rev or restrain: Mechanisms of human-specific synaptic neoteny. 修正或抑制：人类特异性突触新生的机制。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 DOI: 10.1016/j.neuron.2024.10.011

Jenelle L Wallace, Alex A Pollen

引用次数: 0

Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons. 群体失灵：尽管组成神经元保持稳定，但牛磺酸病破坏了突发动力学中的稳态设定点。

IF 3.784 1区医学

Neuron Pub Date : 2024-11-06 Epub Date: 2024-09-05 DOI: 10.1016/j.neuron.2024.08.006

James N McGregor, Clayton A Farris, Sahara Ensley, Aidan Schneider, Leandro J Fosque, Chao Wang, Elizabeth I Tilden, Yuqi Liu, Jianhong Tu, Halla Elmore, Keenan D Ronayne, Ralf Wessel, Eva L Dyer, Kiran Bhaskaran-Nair, David M Holtzman, Keith B Hengen

{"title":"Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons.","authors":"James N McGregor, Clayton A Farris, Sahara Ensley, Aidan Schneider, Leandro J Fosque, Chao Wang, Elizabeth I Tilden, Yuqi Liu, Jianhong Tu, Halla Elmore, Keenan D Ronayne, Ralf Wessel, Eva L Dyer, Kiran Bhaskaran-Nair, David M Holtzman, Keith B Hengen","doi":"10.1016/j.neuron.2024.08.006","DOIUrl":"10.1016/j.neuron.2024.08.006","url":null,"abstract":"Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal's genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3567-3584.e5"},"PeriodicalIF":3.784,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146076","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

Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments. 肠道诱导的α-突触核蛋白和Tau传播引发帕金森病和阿尔茨海默病的共同病理学和行为障碍。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 Epub Date: 2024-09-05 DOI: 10.1016/j.neuron.2024.08.003

Jie Xiang, Jingrong Tang, Fei Kang, Jiajun Ye, Yueying Cui, Zhentao Zhang, Jing Wang, Shengxi Wu, Keqiang Ye

{"title":"Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments.","authors":"Jie Xiang, Jingrong Tang, Fei Kang, Jiajun Ye, Yueying Cui, Zhentao Zhang, Jing Wang, Shengxi Wu, Keqiang Ye","doi":"10.1016/j.neuron.2024.08.003","DOIUrl":"10.1016/j.neuron.2024.08.003","url":null,"abstract":"Tau interacts with α-Synuclein (α-Syn) and co-localizes with it in the Lewy bodies, influencing α-Syn pathology in Parkinson's disease (PD). However, whether these biochemical events regulate α-Syn pathology spreading from the gut into the brain remains incompletely understood. Here, we show that α-Syn and Tau co-pathology is spread into the brain in gut-inducible SYN103+/- and/or TAU368+/- transgenic mouse models, eliciting behavioral defects. Gut pathology was initially observed, and α-Syn or Tau pathology was subsequently propagated into the DMV or NTS and then to other brain regions. Remarkably, more extensive spreading and widespread neuronal loss were found in double transgenic mice (Both) than in single transgenic mice. Truncal vagotomy and α-Syn deficiency significantly inhibited synucleinopathy or tauopathy spreading. The α-Syn PET tracer [18F]-F0502B detected α-Syn aggregates in the gut and brain. Thus, α-Syn and Tau co-pathology can propagate from the gut to the brain, triggering behavioral disorders.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"3585-3601.e5"},"PeriodicalIF":14.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146077","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

Integration and competition between space and time in the hippocampus. 海马中空间与时间的整合与竞争

IF 14.7 1区医学

Neuron Pub Date : 2024-11-06 Epub Date: 2024-09-05 DOI: 10.1016/j.neuron.2024.08.007

Shijie Chen, Ning Cheng, Xiaojing Chen, Cheng Wang

引用次数: 0

NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics. NMDA 受体在不改变单细胞动力学的情况下调节海马回路的点燃率设定点。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-05 DOI: 10.1016/j.neuron.2024.10.014

Antonella Ruggiero, Leore R Heim, Lee Susman, Dema Hreaky, Ilana Shapira, Maxim Katsenelson, Kobi Rosenblum, Inna Slutsky

{"title":"NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics.","authors":"Antonella Ruggiero, Leore R Heim, Lee Susman, Dema Hreaky, Ilana Shapira, Maxim Katsenelson, Kobi Rosenblum, Inna Slutsky","doi":"10.1016/j.neuron.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.neuron.2024.10.014","url":null,"abstract":"Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604624","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

Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias. 氧化还原调节、蛋白质 S-亚硝基化和阿尔茨海默氏症及相关痴呆症的突触丧失。

IF 14.7 1区医学

Neuron Pub Date : 2024-11-05 DOI: 10.1016/j.neuron.2024.10.013

Chang-Ki Oh, Tomohiro Nakamura, Xu Zhang, Stuart A Lipton

{"title":"Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias.","authors":"Chang-Ki Oh, Tomohiro Nakamura, Xu Zhang, Stuart A Lipton","doi":"10.1016/j.neuron.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.neuron.2024.10.013","url":null,"abstract":"Redox-mediated posttranslational modification, as exemplified by protein S-nitrosylation, modulates protein activity and function in both health and disease. Here, we review recent findings that show how normal aging, infection/inflammation, trauma, environmental toxins, and diseases associated with protein aggregation can each trigger excessive nitrosative stress, resulting in aberrant protein S-nitrosylation and hence dysfunctional protein networks. These redox reactions contribute to the etiology of multiple neurodegenerative disorders as well as systemic diseases. In the CNS, aberrant S-nitrosylation reactions of single proteins or, in many cases, interconnected networks of proteins lead to dysfunctional pathways affecting endoplasmic reticulum (ER) stress, inflammatory signaling, autophagy/mitophagy, the ubiquitin-proteasome system, transcriptional and enzymatic machinery, and mitochondrial metabolism. Aberrant protein S-nitrosylation and transnitrosylation (transfer of nitric oxide [NO]-related species from one protein to another) trigger protein aggregation, neuronal bioenergetic compromise, and microglial phagocytosis, all of which contribute to the synapse loss that underlies cognitive decline in Alzheimer's disease and related dementias.","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604715","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

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