Science Translational Medicine最新文献

{"title":"Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution","authors":"Rebecca E. Hamlin, Shaun M. Pienkos, Leslie Chan, Mikayla A. Stabile, Kassandra Pinedo, Mallika Rao, Philip Grant, Hector Bonilla, Marisa Holubar, Upinder Singh, Karen B. Jacobson, Prasanna Jagannathan, Yvonne Maldonado, Susan P. Holmes, Aruna Subramanian, Catherine A. Blish","doi":"10.1126/scitranslmed.adr1032","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr1032","url":null,"abstract":"Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced <jats:italic>TGFB1</jats:italic> expression. Females who developed LC demonstrated increased expression of <jats:italic>XIST</jats:italic> , an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced <jats:italic>ETS1</jats:italic> expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that <jats:italic>ETS1</jats:italic> alterations may drive aberrantly elevated T helper cell 2–like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"36 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601973","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}

{"title":"Sex differences in postacute infection syndromes","authors":"Julio Silva, Akiko Iwasaki","doi":"10.1126/scitranslmed.ado2102","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2102","url":null,"abstract":"Postacute infection syndromes like Long Covid disproportionately affect females, differing in prevalence, symptoms, and potential causes from males. This Viewpoint highlights these sex differences, gaps in current understanding, and the critical need for sex-based research.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"63 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601974","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}

{"title":"Initiating Long Covid RECOVERy.","authors":"Jeanne Marrazzo, Gary H Gibbons, Walter Koroshetz","doi":"10.1126/scitranslmed.adr9971","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr9971","url":null,"abstract":"<p><p>The NIH's RECOVER Initiative aims to ease the suffering of those living with Long Covid.</p>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 773","pages":"eadr9971"},"PeriodicalIF":15.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142626793","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}

{"title":"Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients","authors":"Luke C. Bartelt,&nbsp;Pawel M. Switonski,&nbsp;Grażyna Adamek,&nbsp;Fabiana Longo,&nbsp;Juliana Carvalho,&nbsp;Lisa A. Duvick,&nbsp;Sabrina I. Jarrah,&nbsp;Hayley S. McLoughlin,&nbsp;Daniel R. Scoles,&nbsp;Stefan M. Pulst,&nbsp;Harry T. Orr,&nbsp;Court Hull,&nbsp;Craig B. Lowe,&nbsp;Albert R. La Spada","doi":"10.1126/scitranslmed.adn5449","DOIUrl":"10.1126/scitranslmed.adn5449","url":null,"abstract":"<div >Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588533","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}

{"title":"Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection","authors":"Christopher D. Petro,&nbsp;Andrea T. Hooper,&nbsp;Avery Peace,&nbsp;Kusha Mohammadi,&nbsp;Will Eagan,&nbsp;Sayda M. Elbashir,&nbsp;Anthony DiPiazza,&nbsp;Daniel Makrinos,&nbsp;Kristen Pascal,&nbsp;Pooja Bandawane,&nbsp;Mauricio Durand,&nbsp;Ranu Basu,&nbsp;Alida Coppi,&nbsp;Bei Wang,&nbsp;Jacquelynn Golubov,&nbsp;Seblewongel Asrat,&nbsp;Samit Ganguly,&nbsp;Ellen-Marie Koehler-Stec,&nbsp;Matthew F. Wipperman,&nbsp;George Ehrlich,&nbsp;Ana M. Gonzalez Ortiz,&nbsp;Flonza Isa,&nbsp;Mark G. Lewis,&nbsp;Hanne Andersen,&nbsp;Bret J. Musser,&nbsp;Marcela Torres,&nbsp;Wen-Yi Lee,&nbsp;Darin Edwards,&nbsp;Dimitris Skokos,&nbsp;Jamie Orengo,&nbsp;Matthew Sleeman,&nbsp;Thomas Norton,&nbsp;Meagan O’Brien,&nbsp;Eduardo Forleo-Neto,&nbsp;Gary A. Herman,&nbsp;Jennifer D. Hamilton,&nbsp;Andrew J. Murphy,&nbsp;Christos A. Kyratsous,&nbsp;Alina Baum","doi":"10.1126/scitranslmed.adn0396","DOIUrl":"10.1126/scitranslmed.adn0396","url":null,"abstract":"<div >Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein–directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti–spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2–infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588797","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}

{"title":"Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population","authors":"Jingjing Ding,&nbsp;Huaizheng Liu,&nbsp;Xiaoxun Zhang,&nbsp;Nan Zhao,&nbsp;Ying Peng,&nbsp;Junping Shi,&nbsp;Jinjun Chen,&nbsp;Xiaoling Chi,&nbsp;Ling Li,&nbsp;Mengni Zhang,&nbsp;Wen-Yue Liu,&nbsp;Liangjun Zhang,&nbsp;Jiafeng Ouyang,&nbsp;Qian Yuan,&nbsp;Min Liao,&nbsp;Ya Tan,&nbsp;Mingqiao Li,&nbsp;Ziqian Xu,&nbsp;Wan Tang,&nbsp;Chuanming Xie,&nbsp;Yi Li,&nbsp;Qiong Pan,&nbsp;Ying Xu,&nbsp;Shi-Ying Cai,&nbsp;Christopher D. Byrne,&nbsp;Giovanni Targher,&nbsp;Xinshou Ouyang,&nbsp;Liqun Zhang,&nbsp;Zhongyong Jiang,&nbsp;Ming-Hua Zheng,&nbsp;Fengjun Sun,&nbsp;Jin Chai","doi":"10.1126/scitranslmed.adh9940","DOIUrl":"10.1126/scitranslmed.adh9940","url":null,"abstract":"<div >Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid–mTOR–FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588798","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}

{"title":"Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19","authors":"Benjamin R. Babcock,&nbsp;Astrid Kosters,&nbsp;Devon J. Eddins,&nbsp;Maria Sophia Baluyot Donaire,&nbsp;Sannidhi Sarvadhavabhatla,&nbsp;Vivian Pae,&nbsp;Fiona Beltran,&nbsp;Victoria W. Murray,&nbsp;Gurjot Gill,&nbsp;Guorui Xie,&nbsp;Brian S. Dobosh,&nbsp;Vincent D. Giacalone,&nbsp;Rabindra M. Tirouvanziam,&nbsp;Richard P. Ramonell,&nbsp;Scott A. Jenks,&nbsp;Ignacio Sanz,&nbsp;F. Eun-Hyung Lee,&nbsp;Nadia R. Roan,&nbsp;Sulggi A. Lee,&nbsp;Eliver E. B. Ghosn","doi":"10.1126/scitranslmed.adq1789","DOIUrl":"10.1126/scitranslmed.adq1789","url":null,"abstract":"<div >Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588499","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}

{"title":"Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice","authors":"Victor Fattori,&nbsp;Tiago H. Zaninelli,&nbsp;Fernanda S. Rasquel-Oliveira,&nbsp;Olivia K. Heintz,&nbsp;Ashish Jain,&nbsp;Liang Sun,&nbsp;Maya L. Seshan,&nbsp;Daniëlle Peterse,&nbsp;Anne E. Lindholm,&nbsp;Raymond M. Anchan,&nbsp;Waldiceu A. Verri Jr.,&nbsp;Michael S. Rogers","doi":"10.1126/scitranslmed.adk8230","DOIUrl":"10.1126/scitranslmed.adk8230","url":null,"abstract":"<div >Endometriosis is a debilitating and painful gynecological inflammatory disease affecting up to 15% of women and transgender men. Current treatments are ineffective for a substantial proportion of patients, underscoring the need for additional therapies with long-term benefits. Nociceptors release neuropeptides, such as calcitonin gene–related peptide (CGRP), which are known to shape immunity through neuroimmune communication. Given the comorbidity between endometriosis and migraine and the integral role of immune cells and inflammation in endometriosis, we investigated the role of CGRP-mediated neuroimmune communication in endometriosis. Using samples from eight patients with endometriosis and a nonsurgical mouse model of the disease, we found that mouse and human endometriosis lesions contain both CGRP and its coreceptor, receptor activity modifying protein 1 (RAMP1). In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptor activation and neuropeptide release contribute to endometriosis lesion growth and pain. Mechanistically, CGRP changed the phenotype of macrophages to a pro-endometriosis phenotype. CGRP-stimulated macrophages demonstrated impaired efferocytosis and supported increased endometrial cell growth in a RAMP1-dependent manner. Treatment of lesion-bearing mice with US Food and Drug Administration–approved drugs that block CGRP-RAMP1 signaling reduced mechanical hyperalgesia, spontaneous pain, and lesion size. Together, our data demonstrated the effectiveness and underlying cellular mechanisms of nonhormonal and nonopioid CGRP/RAMP1 blockade in a mouse model of endometriosis, suggesting that targeting this axis may lead to clinical benefit for patients with endometriosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588503","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}

{"title":"The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice","authors":"Rebecca L. Wallings,&nbsp;Karen McFarland,&nbsp;Hannah A. Staley,&nbsp;Noelle Neighbarger,&nbsp;Susen Schaake,&nbsp;Norbert Brüggemann,&nbsp;Simone Zittel,&nbsp;Tatiana Usnich,&nbsp;Christine Klein,&nbsp;Esther M. Sammler,&nbsp;Malú Gámez Tansey","doi":"10.1126/scitranslmed.adl1535","DOIUrl":"10.1126/scitranslmed.adl1535","url":null,"abstract":"<div >Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the <i>LRRK2</i> gene affects risk for both familial and sporadic Parkinson’s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from <i>R1441C-Lrrk2</i> knock-in mice and observed a biphasic, age-dependent effect of the <i>R1441C-Lrrk2</i> mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female <i>R1441C-Lrrk2</i> mice. Conversely, macrophages from aged (18- to 21-month-old) female <i>R1441C-Lrrk2</i> mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male <i>R1441C-Lrrk2</i> mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the <i>R1441C-</i> or <i>Y1699C-LRRK2</i> mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 772","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl1535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588796","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}

{"title":"Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains","authors":"Biqing Zhu,&nbsp;Jae-Min Park,&nbsp;Sarah R. Coffey,&nbsp;Anthony Russo,&nbsp;I-Uen Hsu,&nbsp;Jiawei Wang,&nbsp;Chang Su,&nbsp;Rui Chang,&nbsp;TuKiet T. Lam,&nbsp;Pallavi P. Gopal,&nbsp;Stephen D. Ginsberg,&nbsp;Hongyu Zhao,&nbsp;David A. Hafler,&nbsp;Sreeganga S. Chandra,&nbsp;Le Zhang","doi":"10.1126/scitranslmed.abo1997","DOIUrl":"10.1126/scitranslmed.abo1997","url":null,"abstract":"<div >Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547169","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}