Christina Kratzmeier,Mojtaba Taheri,Zhongcheng Mei,Isabelle Lim,May A Khalil,Brandon Carter-Cooper,Rachel E Fanaroff,Chin S Ong,Eric B Schneider,Stephanie Chang,Erica Leyder,Dongge Li,Irina G Luzina,Anirban Banerjee,Alexander Sasha Krupnick
{"title":"Lung adenocarcinoma-derived IFN-γ promotes growth by modulating CD8+ T cell production of CCR5 chemokines.","authors":"Christina Kratzmeier,Mojtaba Taheri,Zhongcheng Mei,Isabelle Lim,May A Khalil,Brandon Carter-Cooper,Rachel E Fanaroff,Chin S Ong,Eric B Schneider,Stephanie Chang,Erica Leyder,Dongge Li,Irina G Luzina,Anirban Banerjee,Alexander Sasha Krupnick","doi":"10.1172/jci191070","DOIUrl":"https://doi.org/10.1172/jci191070","url":null,"abstract":"Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shipra Shukla,Dan Li,Woo Hyun Cho,Dana M Schoeps,Holly M Nguyen,Jennifer L Conner,Marjorie L Roskes,Anisha Tehim,Gabriella Bayshtok,Mohini R Pachai,Juan Yan,Nicholas A Teri,Eric Campeau,Sarah Attwell,Patrick Trojer,Irina Ostrovnaya,Anuradha Gopalan,Ekta Khurana,Eva Corey,Ping Chi,Yu Chen
{"title":"BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer.","authors":"Shipra Shukla,Dan Li,Woo Hyun Cho,Dana M Schoeps,Holly M Nguyen,Jennifer L Conner,Marjorie L Roskes,Anisha Tehim,Gabriella Bayshtok,Mohini R Pachai,Juan Yan,Nicholas A Teri,Eric Campeau,Sarah Attwell,Patrick Trojer,Irina Ostrovnaya,Anuradha Gopalan,Ekta Khurana,Eva Corey,Ping Chi,Yu Chen","doi":"10.1172/jci180378","DOIUrl":"https://doi.org/10.1172/jci180378","url":null,"abstract":"A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"187 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soumya Poddar,Jiali Yan,Gayatri Tiwari,Darawan Rinchai,Justin Budka,Wangshu Zhang,Weixin Peng,Shruti Salunkhe,Madison Davis,Qinghua Song,Sara Beygi,Harry Miao,Mike Mattie,Rhine S Shen,Caron A Jacobson,Davide Bedognetti,Simone Filosto,Sattva S Neelapu
{"title":"Clinical, tumor and product features associated with outcomes after axicabtagene ciloleucel therapy in follicular lymphoma.","authors":"Soumya Poddar,Jiali Yan,Gayatri Tiwari,Darawan Rinchai,Justin Budka,Wangshu Zhang,Weixin Peng,Shruti Salunkhe,Madison Davis,Qinghua Song,Sara Beygi,Harry Miao,Mike Mattie,Rhine S Shen,Caron A Jacobson,Davide Bedognetti,Simone Filosto,Sattva S Neelapu","doi":"10.1172/jci181893","DOIUrl":"https://doi.org/10.1172/jci181893","url":null,"abstract":"BACKGROUNDAxicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B-cell lymphomas in the ZUMA-5 trial.METHODSHere, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 follicular lymphoma (FL) patients.RESULTSIn univariate and multivariate analyses, pre-treatment inflammatory markers, including TNFα and IL12p40, as well as total metabolic tumor volume (TMTV) associated with disease progression. Conversely, T-naïve-like product phenotype associated with improved outcome, particularly in high TMTV patients. These covariates improved risk stratification when combined with the FL International Prognostic Index. Post-infusion, CAR T-cell expansion associated with improved outcome, while serum inflammatory and immuno-modulatory markers, including TNFα associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or post-treatment CD19 expression on tumor was not associated with outcome.CONCLUSIONThese findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.TRIAL REGISTRATIONCLINICALTRIALSgov NCT03105336.FUNDINGKite, a Gilead Company. .","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shyam Ramachandran,Jeffery Ardinger,Jie Bu,MiAngela Ramos,Lilu Guo,Dhiman Ghosh,Mahmud Hossain,Shih-Ching Chou,Yao Chen,Erik Wischhof,Swathi Ayloo,Roger Trullo,Yuxia Luo,Jessica M Hogestyn,Daniel M DuBreuil,Emily Crosier,Johanna G Flyer-Adams,Amy M Richards,Michael Tsabar,Giorgio Gaglia,Shelley Nass,Bindu Nambiar,Denise Woodcock,Catherine O'Riordan,Qi Tang,Bradford Elmer,Bailin Zhang,Martin Goulet,Christian Mueller
{"title":"Cross-species efficacy of AAV-mediated ARSA replacement for Metachromatic Leukodystrophy.","authors":"Shyam Ramachandran,Jeffery Ardinger,Jie Bu,MiAngela Ramos,Lilu Guo,Dhiman Ghosh,Mahmud Hossain,Shih-Ching Chou,Yao Chen,Erik Wischhof,Swathi Ayloo,Roger Trullo,Yuxia Luo,Jessica M Hogestyn,Daniel M DuBreuil,Emily Crosier,Johanna G Flyer-Adams,Amy M Richards,Michael Tsabar,Giorgio Gaglia,Shelley Nass,Bindu Nambiar,Denise Woodcock,Catherine O'Riordan,Qi Tang,Bradford Elmer,Bailin Zhang,Martin Goulet,Christian Mueller","doi":"10.1172/jci185001","DOIUrl":"https://doi.org/10.1172/jci185001","url":null,"abstract":"Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated viral vectors (AAV) have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of non-human primates (NHPs). Next, we show that AAV.GMU01-ARSA treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well-tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlin M Stewart,Sonya Parpart-Li,James R White,Mitesh Patel,Oliver Artz,Michael B Foote,Erika Gedvilaite,Michelle F Lamendola-Essel,Drew Gerber,Rohini Bhattacharya,Justin M Haseltine,Kety Huberman,Kelly L Bolton,Ross L Levine,Luis A Diaz
{"title":"Clonal hematopoiesis detection by simultaneous assessment of peripheral blood mononuclear cells, blood plasma, and saliva.","authors":"Caitlin M Stewart,Sonya Parpart-Li,James R White,Mitesh Patel,Oliver Artz,Michael B Foote,Erika Gedvilaite,Michelle F Lamendola-Essel,Drew Gerber,Rohini Bhattacharya,Justin M Haseltine,Kety Huberman,Kelly L Bolton,Ross L Levine,Luis A Diaz","doi":"10.1172/jci191256","DOIUrl":"https://doi.org/10.1172/jci191256","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rudy J Castellani,Hinda Najem,Amy B Heimberger,Pouya Jamshidi
{"title":"Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy.","authors":"Rudy J Castellani,Hinda Najem,Amy B Heimberger,Pouya Jamshidi","doi":"10.1172/jci195137","DOIUrl":"https://doi.org/10.1172/jci195137","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"606 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ekaterina I Mokhonova,Daniel Helzer,Ravinder Malik,Hafsa Mamsa,Jackson Walker,Mark Maslanka,Tess S Fleser,Mohammad H Afsharinia,Shiheng Liu,Johan Holmberg,Z Hong Zhou,Eric J Deeds,Kirk C Hansen,Elizabeth M McNally,Rachelle H Crosbie
{"title":"Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.","authors":"Ekaterina I Mokhonova,Daniel Helzer,Ravinder Malik,Hafsa Mamsa,Jackson Walker,Mark Maslanka,Tess S Fleser,Mohammad H Afsharinia,Shiheng Liu,Johan Holmberg,Z Hong Zhou,Eric J Deeds,Kirk C Hansen,Elizabeth M McNally,Rachelle H Crosbie","doi":"10.1172/jci187868","DOIUrl":"https://doi.org/10.1172/jci187868","url":null,"abstract":"The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well-established that genetic mutations that disrupt the structural integrity of DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25-kDa tetraspanin-like protein, anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protect the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Megan E Capozzi,David Bouslov,Ashot Sargsyan,Michelle Y Chan,Sarah M Gray,Katrina Viloria,Akshay Bareja,Jonathan D Douros,Sophie L Lewandowski,Jason Cl Tong,Annie Hasib,Federica Cuozzo,Elizabeth C Ross,Matthew W Foster,Lee S Weinstein,Mehboob A Hussain,Matthew J Merrins,Francis S Willard,Mark O Huising,Kyle W Sloop,David J Hodson,David A D'Alessio,Jonathan E Campbell
{"title":"β-cell Gɑs signaling is critical for physiological and pharmacological enhancement of insulin secretion.","authors":"Megan E Capozzi,David Bouslov,Ashot Sargsyan,Michelle Y Chan,Sarah M Gray,Katrina Viloria,Akshay Bareja,Jonathan D Douros,Sophie L Lewandowski,Jason Cl Tong,Annie Hasib,Federica Cuozzo,Elizabeth C Ross,Matthew W Foster,Lee S Weinstein,Mehboob A Hussain,Matthew J Merrins,Francis S Willard,Mark O Huising,Kyle W Sloop,David J Hodson,David A D'Alessio,Jonathan E Campbell","doi":"10.1172/jci183741","DOIUrl":"https://doi.org/10.1172/jci183741","url":null,"abstract":"The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors coordinate β-cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gɑs protein and generation of intracellular cyclic adenosine monophosphate (cAMP). However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G-proteins and β-arrestin proteins. Here, the importance of Gɑs signaling was tested in mice with conditional, post-developmental β-cell deletion of Gnas (encoding Gɑs) under physiological and pharmacological conditions. Deletion of Gɑs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine and IBMX. In the absence of Gɑs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gɑq signaling. Collectively, these findings validate a central role for cAMP to mediate incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gɑs that causes both fasting hyperglycemia and glucose intolerance.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dae-Seok Kim,Toshiharu Onodera,Jan-Bernd Funcke,Kyounghee Min,Qingzhang Zhu,Qian Lin,Shiuhwei Chen,Chanmin Joung,Min Kim,R Max Wynn,Joselin Velasco,Charlotte Lee,Megan Virostek,Chao Li,Philipp E Scherer
{"title":"Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice.","authors":"Dae-Seok Kim,Toshiharu Onodera,Jan-Bernd Funcke,Kyounghee Min,Qingzhang Zhu,Qian Lin,Shiuhwei Chen,Chanmin Joung,Min Kim,R Max Wynn,Joselin Velasco,Charlotte Lee,Megan Virostek,Chao Li,Philipp E Scherer","doi":"10.1172/jci187202","DOIUrl":"https://doi.org/10.1172/jci187202","url":null,"abstract":"Pro-inflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the anti-inflammatory adenoviral RIDα/β protein complex in a cell type-specific manner. Suppression of adipocyte inflammation (\"RIDad mice\") in a mammary tumor model driven by MMTV-PyMT (\"PyMT-RIDad mice\") led to an elevated number of tumor-associated macrophages (TAMs) and upregulation of immunoregulatory molecules in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (\"RIDMMTV mice\") decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TianMeng Xu,Rachel Heon-Roberts,Travis Moore,Patricia Dubot,Xuefang Pan,Tianlin Guo,Christopher W Cairo,Rebecca J Holley,Brian Bigger,Thomas M Durcan,Thierry Levade,Jerôme Ausseil,Bénédicte Amilhon,Alexei Gorelik,Bhushan Nagar,Shaukat Khan,Shunji Tomatsu,Luisa Sturiale,Angelo Palmigiano,Iris Röckle,Hauke Thiesler,Herbert Hildebrandt,Domenico Garozzo,Alexey V Pshezhetsky
{"title":"Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain proteins hypersialylation.","authors":"TianMeng Xu,Rachel Heon-Roberts,Travis Moore,Patricia Dubot,Xuefang Pan,Tianlin Guo,Christopher W Cairo,Rebecca J Holley,Brian Bigger,Thomas M Durcan,Thierry Levade,Jerôme Ausseil,Bénédicte Amilhon,Alexei Gorelik,Bhushan Nagar,Shaukat Khan,Shunji Tomatsu,Luisa Sturiale,Angelo Palmigiano,Iris Röckle,Hauke Thiesler,Herbert Hildebrandt,Domenico Garozzo,Alexey V Pshezhetsky","doi":"10.1172/jci177430","DOIUrl":"https://doi.org/10.1172/jci177430","url":null,"abstract":"Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII, associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brains of MPS patients and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe to be a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"608 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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