JCI insight最新文献

{"title":"HSP70 is a chaperone for IL-33 activity in chronic airway disease.","authors":"Omar A Osorio, Heather E Raphael, Colin E Kluender, Ghandi F Hassan, Lucy S Cohen, Deborah F Steinberg, Ella Katz-Kiriakos, Morgan D Payne, Ethan M Luo, Jamie L Hicks, Derek E Byers, Jennifer Alexander-Brett","doi":"10.1172/jci.insight.193640","DOIUrl":"10.1172/jci.insight.193640","url":null,"abstract":"<p><p>IL-33 is a key driver of type-2 inflammation and implicated in pathology of COPD and asthma. However, the mechanism for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. We previously reported an airway disease-associated isoform IL-33Δ34 that escapes nuclear sequestration and is tonically secreted from epithelial cells. Here, we describe how this IL-33Δ34 isoform interacts with HSP70 within cells and is targeted to secretory organelles through coordinated binding to phosphatidylserine (PS), and delivered to compartments for unconventional protein secretion (CUPS). Once secreted, extracellular HSP70 (eHSP70) in complex with IL-33Δ34 stabilizes cytokine by inhibiting oxidation and degradation, which results in enhanced IL-33Δ34-receptor binding and activity. We further find evidence that IL-33 along with mediators of the proteostasis network HSP70, HSP90 and the Chaperonin Containing TCP1 (CCT) complex are dysregulated in human chronic airway disease. This phenomenon is reflected in the differential extracellular vesicle (EV) proteome in bronchial wash from COPD and asthma samples, which could mark disease activity and potentiate IL-33 function. This study confirms proteostasis intermediates, chiefly HSP70, as a chaperone for non-canonical IL-33 secretion and activity that may be amenable for therapeutic targeting in the chronic airway diseases COPD and asthma.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484409","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":"LRP2 is a potential molecular target for nonsyndromic pathological myopia.","authors":"Kimberley Delaunay, Emilie Picard, Patricia Lassiaz, Laurent Jonet, Vidjea Cannaya, José Maria Ruiz-Moreno, Kentaro Kojima, Henrik Vorum, Bent Honoré, Jorge R Medrano, Lasse Jørgensen Cehofski, Eric Pussard, Renata Kozyraki, Alicia Torriglia, Olivier Cases, Francine Behar-Cohen","doi":"10.1172/jci.insight.192929","DOIUrl":"https://doi.org/10.1172/jci.insight.192929","url":null,"abstract":"<p><p>High myopia (HM) and posterior staphyloma (PS) are major causes of vision loss worldwide. Genetic and environmental factors, especially light exposure, influence myopia. This study shows that LRP2 (Low-density lipoprotein-related receptor type 2) levels are decreased in the vitreous of patients with HM and PS, and that in human donor eyes affected by PS, LRP2 expression was reduced in the neural retina and retinal pigment epithelium (RPE), with morphologic changes similar to those observed in the Foxg1-Cre-Lrp2lox/lox mouse that also develops PS. In human iPSc-derived RPE cells (iRPE), LRP2 silencing regulated genes involved in eye and neuronal development, visual perception, tissue remodeling, hormone metabolism and RPE structure. Its expression increased under light exposure, particularly red light, but was downregulated by cortisol. These findings establish a link between LRP2, myopization, and environmental factors, highlighting its crucial role in nonsyndromic HM and PS. LRP2 appears to be a promising therapeutic target for high myopia treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484411","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":"An insider's guide to understanding and obtaining an NIH K career development award.","authors":"Don C Rockey, Kyu Y Rhee, Christopher S Williams, Jatin M Vyas, Charles W Emala, Emily J Gallagher","doi":"10.1172/jci.insight.191904","DOIUrl":"10.1172/jci.insight.191904","url":null,"abstract":"<p><p>Physician-scientists in academic medical centers require extramural grant support to launch and maintain their research careers. In order to cultivate the next generation of biomedical researchers, including physician-scientists, the NIH supports multiple career development (K series) awards. For many, their first experience in grant writing is composing a career development award (CDA) application. From the applicant's perspective, this process can be difficult. For one, NIH institute-specific differences between the same K mechanism can be confusing. Additionally, the importance of the various elements that make up the K application are frequently misunderstood. Furthermore, many K applications will not be funded on the initial submission; therefore, the need to resubmit an application should not be viewed as a sign of failure, but rather can be viewed as an element of resilience in biomedical research. In this piece, we aim to provide guidance for aspiring K applicants - in particular, from the reviewer perspective - with the intent of making the application process more understandable. We offer dos and don'ts on different components of the K application, advice on when to reach out to a program officer, and tips on resubmission. Our overarching goal is to provide support for prospective K applicants in their effort to obtain a K award. While targeted to K applications, most of the contents of this summary apply to any CDA.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475284","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":"Resident memory T cell development is gradual and shows AP-1 gene expression in mature cells.","authors":"Neal P Smith, Yu Yan, Youdong Pan, Jason B Williams, Kasidet Manakongtreecheep, Shishir M Pant, Jingxia Zhao, Tian Tian, Timothy Pan, Claire Stingley, Kevin Wu, Jiang Zhang, Alexander L Kley, Peter K Sorger, Alexandra-Chloé Villani, Thomas S Kupper","doi":"10.1172/jci.insight.187381","DOIUrl":"10.1172/jci.insight.187381","url":null,"abstract":"<p><p>Tissue-resident memory T (TRM) cells play a central role in immune responses across all barrier tissues after infection. However, the mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged newly generated and publicly available single-cell RNA-seq data generated across 10 developmental time points to define features of CD8+ TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture gene programs that increase their expression levels in T cells transitioning from an effector to a memory state. In addition to capturing tissue-specific gene programs, we defined a temporal TRM signature across skin and siIEL that can distinguish TRM from circulating T cell populations. This TRM signature highlights biology that is missed in published signatures that compared bulk TRM to naive or nontissue resident memory populations. This temporal TRM signature included the AP-1 transcription factor family members Fos, Fosb, Fosl2, and Junb. ATAC-seq analysis detected AP-1-specific motifs at open chromatin sites in mature TRM. Cyclic immunofluorescence (CyCIF) tissue imaging detected nuclear colocalization of AP-1 members in resting CD8+ TRM greater than 100 days after infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475287","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":"A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans.","authors":"Heinrich E Lob, Nikhil Singh, Kusha Mohammadi, Larisa Ivanova, Beth Crowell, Hyon J Kim, Leah Kravets, Nanditha M Das, Yonaton Ray, Jee Hae Kim, Sylvie Rottey, Emily Labriola-Tompkins, Hazem E Hassan, Lorna Farrelly, Harvey F Chin, Marilena Preda, Leigh Spencer Noakes, Kei Saotome, Matthew Franklin, Marc W Retter, Elif Karayusuf, John J Flanagan, William Olson, Kalyan C Nannuru, Vincent Idone, Michael E Burczynski, Olivier A Harari, Lorah Perlee, Griet Van Lancker, Andrew J Murphy, Aris N Economides, Sarah J Hatsell","doi":"10.1172/jci.insight.191813","DOIUrl":"10.1172/jci.insight.191813","url":null,"abstract":"<p><p>β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475283","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":"Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state.","authors":"Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada","doi":"10.1172/jci.insight.187424","DOIUrl":"10.1172/jci.insight.187424","url":null,"abstract":"<p><p>Pancreatic stellate cells (PSCs) are the origin of cancer-associated fibroblasts. Type 2 diabetes mellitus (T2D) may promote pancreatic ductal adenocarcinoma (PDAC), eliciting changes in the quiescent PSC (qPSC) population from the precancerous stage. However, the details are unknown. We evaluated the subpopulations of qPSCs and the impact of T2D. PSCs isolated from 8-week-old C57BL/6J mice and diabetic db/db mice were analyzed by single-cell RNA-seq. Sorted qPSCs and PDAC cells were transplanted into allogenic mice. The isolated qPSCs were broadly classified into mesothelial cell and pancreatic fibroblast (Paf) populations by single-cell RNA-seq. Pafs were subclassified into inflammatory Pafs, myofibroblastic Pafs (myPafs) and a small population named tumor immunity- and angiogenesis-promoting Pafs (tapPafs), expressing Cxcl13. In the subcutaneous transplantation model, the tumors transplanted with myPafs were significantly larger than the tumors transplanted with tapPafs. An increase in myPafs and a decrease in tapPafs were observed from the precancerous stage in human T2D, indicating the effects of tumor progression. This study revealed the subpopulation changes in qPSCs in T2D. A therapy that increases the number of tapPafs could be a therapeutic option for patients with PDAC and T2D and even those in a precancerous stage of T2D.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475290","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":"The distal nephron biomarkers associate with diabetic kidney disease progression.","authors":"Christina L Tamargo, Steven G Coca, Heather Thiessen Philbrook, David G Hu, Joachim H Ix, Michael G Shlipak, Linda F Fried, Orlando M Gutierrez, Sushrut S Waikar, Sarah J Schrauben, Jeffrey R Schelling, Peter Ganz, Paul L Kimmel, Jason H Greenberg, Rajat Deo, Ayumi Takakura, Ramachandran S Vasan, Joseph V Bonventre, Chirag R Parikh","doi":"10.1172/jci.insight.186836","DOIUrl":"10.1172/jci.insight.186836","url":null,"abstract":"<p><p>BACKGROUNDWhile urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial.</p><p><strong>Methods: </strong>We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change.</p><p><strong>Results: </strong>Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30-89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424-1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3-3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels.</p><p><strong>Conclusion: </strong>Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD.</p><p><strong>Trial registration: </strong></p><p><strong>Clinicaltrials: </strong>gov NCT00555217.</p><p><strong>Funding: </strong>NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475289","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":"Lipidomic profiling of human adiposomes identifies specific lipid shifts linked to obesity and cardiometabolic risk.","authors":"Abeer M Mahmoud, Imaduddin Mirza, Elsayed Metwally, Mohammed H Morsy, Giorgia Scichilone, Monica C Asada, Amro Mostafa, Francesco M Bianco, Mohamed M Ali, Mario A Masrur, Chandra Hassan, Brian T Layden","doi":"10.1172/jci.insight.191872","DOIUrl":"10.1172/jci.insight.191872","url":null,"abstract":"<p><p>BACKGROUNDObesity, a growing health concern, often leads to metabolic disturbances, systemic inflammation, and vascular dysfunction. Emerging evidence suggests that adipose tissue-derived extracellular vesicles (adiposomes) may propagate obesity-related complications. However, their lipid composition and effect on cardiometabolic state remain unclear.METHODSThis study examined the lipid composition of adiposomes in 122 participants (75 in obesity group, 47 in lean group) and its connection to cardiometabolic risk. Adiposomes were isolated via ultracentrifugation and characterized using nanoparticle tracking and comprehensive lipidomic analysis by mass spectrometry. Cardiometabolic assessments included anthropometry, body composition, glucose-insulin homeostasis, lipid profiles, inflammatory markers, and vascular function.RESULTSCompared with lean controls, individuals with obesity exhibited elevated adiposome release and shifts in lipid composition, including higher ceramides, free fatty acids, and acylcarnitines, along with reduced levels of phospholipids and sphingomyelins. These alterations strongly correlated with increased BMI, insulin resistance, systemic inflammation, and impaired vascular function. Pathway enrichment analyses highlight dysregulation in glycerophospholipid and sphingolipid metabolism, bile secretion, proinflammatory pathways, and vascular contractility. Machine-learning models utilizing adiposome lipid data accurately classified obesity and predicted cardiometabolic conditions, such as diabetes, hypertension, dyslipidemia, and liver steatosis, achieving accuracy above 85%.CONCLUSIONObesity profoundly remodels the adiposome lipid landscape, linking lipid changes to inflammation, metabolic dysfunction, and vascular impairment. These findings underscore adiposome lipids as biomarkers for obesity and related cardiometabolic disorders, supporting personalized interventions and offering therapeutic value in risk stratification and treatment.FUNDINGThis project was supported by NIH grants R01HL161386, R00HL140049, P30DK020595 (PI: AMM), R01DK104927, and P30DK020595 as well as by a VA Merit Award (1I01BX003382, PI: BTL).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475286","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":"Retraction of Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice.","authors":"Jianqiang Bao, Carlos J Perez, Jeesun Kim, Huan Zhang, Caitlin J Murphy, Tewfik Hamidi, Jean Jaubert, Craig D Platt, Janet Chou, Meichun Deng, Meng-Hua Zhou, Yuying Huang, Héctor Gaitán-Peñas, Jean-Louis Guénet, Kevin Lin, Yue Lu, Taiping Chen, Mark T Bedford, Sharon Yr Dent, John H Richburg, Raúl Estévez, Hui-Lin Pan, Raif S Geha, Qinghua Shi, Fernando Benavides","doi":"10.1172/jci.insight.195729","DOIUrl":"10.1172/jci.insight.195729","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475288","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":"Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy.","authors":"Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno","doi":"10.1172/jci.insight.182123","DOIUrl":"10.1172/jci.insight.182123","url":null,"abstract":"<p><p>Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type-specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of an SBMA mouse model (AR-97Q). Among all cell types, oligodendrocytes had the highest number of differentially expressed genes before disease onset. Analysis of oligodendrocyte clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from oligodendrocytes to neurons in AR-97Q mice compared with wild-type mice. These changes in the early stages were abrogated at the advanced stages. An oligodendrocyte model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization, and Ca2+ imaging of oligodendrocytes in AR-97Q mice revealed the increased Ca2+ responses. A coculture system of primary rat oligodendrocytes and neurons revealed that the mutant AR in oligodendrocytes affected the activity and synchronization of neurons. These findings suggest that dysregulated cell-to-cell communication plays a critical role in early SBMA pathology and that synaptic or ion channel-related proteins, such as contactin associated protein 2 (Cntnap2) and NALCN channel auxiliary factor 1 (Fam155a), are potential therapeutic targets for SBMA.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475285","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}