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2. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity

Author

Vanderbeke, L., Van Mol, P., Van Herck, Y., De Smet, F., Humblet-Baron, S., Martinod, K., Antoranz, A., Arijs, I., Boeckx, B., Bosisio, F. M., Casaer, M., Dauwe, D., De Wever, W., Dooms, C., Dreesen, E., Emmaneel, A., Filtjens, J., Gouwy, M., Gunst, J., Hermans, G., Jansen, S., Lagrou, K., Liston, A., Lorent, N., Meersseman, P., Mercier, T., Neyts, J., Odent, J., Panovska, D., Penttila, P. A., Pollet, E., Proost, P., Qian, J., Quintelier, K., Raes, J., Rex, S., Saeys, Y., Sprooten, J., Tejpar, S., Testelmans, D., Thevissen, K., Van Buyten, T., Vandenhaute, J., Van Gassen, S., Velásquez Pereira, L. C., Vos, R., Weynand, B., Wilmer, A., Yserbyt, J., Garg, A. D., Matthys, P., Wouters, C., Lambrechts, D., Wauters, E., and Wauters, J.

Published
2021
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4. Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy

Author

White, K., primary, Connor, K., additional, Meylan, M., additional, Bougoüin, A., additional, Salvucci, M., additional, Bielle, F., additional, O’Farrell, A.C., additional, Sweeney, K., additional, Weng, L., additional, Bergers, G., additional, Dicker, P., additional, Ashley, D.M., additional, Lipp, E.S., additional, Low, J.T., additional, Zhao, J., additional, Wen, P., additional, Prins, R., additional, Verreault, M., additional, Idbaih, A., additional, Biswas, A., additional, Prehn, J.H.M., additional, Lambrechts, D., additional, Arijs, I., additional, Lodi, F., additional, Dilcan, G., additional, Lamfers, M., additional, Leenstra, S., additional, Fabro, F., additional, Ntafoulis, I., additional, Kros, J.M., additional, Cryan, J., additional, Brett, F., additional, Quissac, E., additional, Beausang, A., additional, MacNally, S., additional, O’Halloran, P., additional, Clerkin, J., additional, Bacon, O., additional, Kremer, A., additional, Chi Yen, R.T., additional, Varn, F.S., additional, Verhaak, R.G.W., additional, Sautès-Fridman, C., additional, Fridman, W.H., additional, and Byrne, A.T., additional

Published
2023
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5. Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes:implications for precision immunotherapy

Author

White, K., Connor, K., Meylan, M., Bougoüin, A., Salvucci, M., Bielle, F., O'Farrell, A. C., Sweeney, K., Weng, L., Bergers, G., Dicker, P., Ashley, D. M., Lipp, E. S., Low, J. T., Zhao, J., Wen, P., Prins, R., Verreault, M., Idbaih, A., Biswas, A., Prehn, J. H.M., Lambrechts, D., Arijs, I., Lodi, F., Dilcan, G., Lamfers, M., Leenstra, S., Fabro, F., Ntafoulis, I., Kros, J. M., Cryan, J., Brett, F., Quissac, E., Beausang, A., MacNally, S., O'Halloran, P., Clerkin, J., Bacon, O., Kremer, A., Chi Yen, R. T., Varn, F. S., Verhaak, R. G.W., Sautès-Fridman, C., Fridman, W. H., Byrne, A. T., White, K., Connor, K., Meylan, M., Bougoüin, A., Salvucci, M., Bielle, F., O'Farrell, A. C., Sweeney, K., Weng, L., Bergers, G., Dicker, P., Ashley, D. M., Lipp, E. S., Low, J. T., Zhao, J., Wen, P., Prins, R., Verreault, M., Idbaih, A., Biswas, A., Prehn, J. H.M., Lambrechts, D., Arijs, I., Lodi, F., Dilcan, G., Lamfers, M., Leenstra, S., Fabro, F., Ntafoulis, I., Kros, J. M., Cryan, J., Brett, F., Quissac, E., Beausang, A., MacNally, S., O'Halloran, P., Clerkin, J., Bacon, O., Kremer, A., Chi Yen, R. T., Varn, F. S., Verhaak, R. G.W., Sautès-Fridman, C., Fridman, W. H., and Byrne, A. T.

Abstract

Background: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. Materials and methods: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. Results: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an ‘immune-desert’ group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunoth

Published
2023

12. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

Author

Arijs, I., Li, K., Toedter, G., Quintens, R., Van Lommel, L., Van Steen, K., Leemans, P., De Hertogh, G., Lemaire, K., Ferrante, M., Schnitzler, F., Thorrez, L., Ma, K., Song, X.-Y.R., Marano, C., Van Assche, G., Vermeire, S., Geboes, K., Schuit, F., Baribaud, F., and Rutgeerts, P.

Subjects
Ulcerative colitis -- Care and treatment, Ulcerative colitis -- Genetic aspects, Ulcerative colitis -- Research, Infliximab -- Dosage and administration, Infliximab -- Research, Immune response -- Genetic aspects, Immune response -- Research, Health
Published
2009

13. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort

Author

Schnitzler, F., Fidder, H., Ferrante, M., Noman, M., Arijs, I., Van Assche, G., Hoffman, I., Van Steen, K., Vermeire, S., and Rutgeerts, P.

Subjects
Crohn's disease -- Care and treatment, Crohn's disease -- Patient outcomes, Crohn's disease -- Research, Infliximab -- Dosage and administration, Infliximab -- Research, Outcome and process assessment (Health Care) -- Research, Health
Published
2009

14. Monocyte-Driven Atypical Cytokine Storm and Aberrant Neutrophil Activation as Key Mediators of COVID19 Disease Severity

Author

Vanderbeke, Lore, primary, Van Mol, Pierre, additional, Van Herck, Y, additional, De Smet, F, additional, Humblet-Baron, S, additional, Martinod, K, additional, Antoranz, A, additional, Arijs, I, additional, Boeckx, B, additional, Bosisio, FM, additional, Casaer, M, additional, Dauwe, D, additional, De Wever, W, additional, Dooms, Christophe, additional, Dreesen, E, additional, Emmaneel, A, additional, Filtjens, J, additional, Gouwy, M, additional, Gunst, J, additional, Hermans, G, additional, Jansen, S, additional, Lagrou, K, additional, Liston, A, additional, Lorent, N, additional, Meersseman, P, additional, Mercier, T, additional, Neyts, J, additional, Odent, J, additional, Panovska, Dena, additional, Penttila, PA, additional, Pollet, E, additional, Proost, P, additional, Qian, J, additional, Quintelier, K, additional, Raes, J, additional, Rex, S, additional, Saeys, Yvan, additional, Sprooten, J, additional, Tejpar, S, additional, Testelmans, D, additional, Thevissen, K, additional, Van Buyten, T, additional, Vandenhaute, J, additional, Van Gassen, S, additional, Velásquez Pereira, LC, additional, Vos, R, additional, Weynand, B, additional, Wilmer, A, additional, Yserbyt, J, additional, Garg, Abhishek, additional, Matthys, P, additional, Wouters, C, additional, Lambrechts, D, additional, Wauters, Els, additional, and Wauters, J, additional

Published
2020
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15. Association between genotypes of rs34436714 of NLRP12 and serum tumor necrosis factor-alpha in inflammatory bowel disease: A case-control study

Author

Dellaporta, E. Lazaridis, L.-D. Koussoulas, V. Netea, M.G. Giamarellos-Bourboulis, E.J. Triantafyllou, K. Arijs, I.

Abstract

We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFα) in patients with inflammatory bowel disease (IBD)In a matched case-control study 90 patients with IBD, 56 with Crohn disease (CD) and 34 with ulcerative colitis, were genotyped and compared to 98 healthy comparators matched for age and gender. Expression level of TNFα, interleukin (IL)-6, IL-12, and soluble triggering receptor expressed on myeloid cells were measured in patients' sera. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for TNFα production.Serum TNFα was greater among carriers of GT/TT genotypes than GG genotypes of rs34436714. Stimulated TNFα production was also higher in carriers of GT/TT genotypes. The frequency of CD with fistulizing behavior and with CD involving the small intestine was greater among carriers of GT/TT genotypes than of the GG genotype. Distribution of the GG, GT, and TT genotypes of rs34436714 were in Hardy-Weinberg equilibrium in both groups. The genotype distribution was the same in both groups.Carriage of minor frequency alleles of rs34436714 was accompanied by greater circulating levels of TNFα and by greater capacity for stimulated TNFα production by PBMCs. These alleles had an impact on the phenotype of patients with CD. © 2019 Oxford University Press. All righs reserved.

Published
2019

23. P096 Analysis of the tryptophan metabolism and indoleamine 2,3-dioxygenase expression (IDO) in patients with inflammatory bowel disease before and after infliximab treatment

Author

Arijs, I., primary, Wollants, W.-J., additional, Clarke, G., additional, Persoons, P., additional, Vanhove, W., additional, Van Lommel, L., additional, Machiels, K., additional, Van Assche, G., additional, Ferrante, M., additional, Schuit, F., additional, Vermeire, S., additional, Rutgeerts, P., additional, and Leuven, K.U., additional

Published
2014
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24. DOP063 Biomarker panel for prediction of mucosal healing in patients with Crohn's disease under infliximab therapy

Author

de Bruyn, M., primary, Bessissow, T., additional, Billiet, T., additional, Cleynen, I., additional, Kirkland, R., additional, Liu, X., additional, Hauenstein, S., additional, Drake, K., additional, Singh, S., additional, Ferrante, M., additional, Rutgeerts, P., additional, Van Assche, G., additional, Arijs, I., additional, Opdenakker, G., additional, and Vermeire, S., additional

Published
2014
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29. OP12 Multiple functional variants at the 3p21 locus contribute to ulcerative colitis: Results from a European consortium

Author

Cleynen, I., primary, Artieda, M., additional, Verspaget, H., additional, Szczypiorska, M., additional, Seibold, F., additional, Lakatos, P., additional, Ahmad, T., additional, Weersma, R., additional, Mahachie, J., additional, Arijs, I., additional, Müller, S., additional, Parnell, K., additional, Tordai, A., additional, Hommes, D.W., additional, Van Steen, K., additional, Wijmenga, C., additional, Rutgeerts, P., additional, Lottaz, D., additional, and Vermeire, S., additional

Published
2012
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31. OP19 Genetic and functional evidence for a role for CYLD in Crohn's disease: Results from a European consortium

Author

Cleynen, I., primary, Vazeille, E., additional, Artieda, M., additional, Szczypiorska, M., additional, Bringer, M.-A., additional, Verspaget, H., additional, Lakatos, P., additional, Seibold, F., additional, Parnell, K., additional, Weersma, R., additional, Mahachie, J., additional, Morgan-Walsh, R., additional, Staelens, D., additional, Arijs, I., additional, Müller, S., additional, Tordai, A., additional, Hommes, D.W., additional, Ahmad, T., additional, Wijmenga, C., additional, Pender, S., additional, Rutgeerts, P., additional, Lottaz, D., additional, Van Steen, K., additional, Vermeire, S., additional, and Darfeuille-Michaud, A., additional

Published
2012
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36. P046 ANALYSIS OF GENETIC VARIANTS IN NON-TPMT GENES TO EXPLAIN BONE MARROW TOXICITY DURING AZATHIOPRINE THERAPY IN INFLAMMATORY BOWEL DISEASE

Author

Katsanos, K., primary, Ferrante, M., additional, Henckaerts, L., additional, Joossens, M., additional, Arijs, I., additional, Schnitzler, F., additional, Fidder, H., additional, Van Assche, G., additional, Katsaraki, A., additional, Christodoulou, D., additional, Tsianos, E., additional, Rutgeerts, P., additional, and Vermeire, S., additional

Published
2008
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37. P189 MICROARRAY STUDY OF MUCOSAL ANTIMICROBIAL PEPTIDES IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE BEFORE AND AFTER FIRST INFLIXIMAB TREATMENT

Author

Arijs, I., primary, Van Lommel, L., additional, Van Steen, K., additional, DeHertogh, G., additional, Quintens, R., additional, Lemaire, K., additional, Joossens, M., additional, Schuit, F., additional, Geboes, K., additional, VanAssche, G., additional, Vermeire, S., additional, and Rutgeerts, P., additional

Published
2008
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45. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity

Author

Patrick Matthys, W. De Wever, Lore Vanderbeke, Paul Proost, Pierre Van Mol, Junbin Qian, M. Casaer, Dena Panovska, Kimberly Martinod, Karin Thevissen, J. Filtjens, Ingrid Arijs, T. Van Buyten, Jenny Sprooten, R. Vos, A. Emmaneel, J. Vandenhaute, Bram Boeckx, Asier Antoranz, J. Odent, L. C. Velásquez Pereira, Yvan Saeys, A. Wilmer, N. Lorent, Diether Lambrechts, Sander Jansen, Jeroen Raes, Abhishek D. Garg, Joost Wauters, Adrian Liston, Erwin Dreesen, Francesca Maria Bosisio, Dieter Dauwe, S. Van Gassen, Birgit Weynand, Els Wauters, K. Quintelier, Dries Testelmans, M. Gouwy, Greet Hermans, Philippe Meersseman, Christophe Dooms, Toine Mercier, Johan Neyts, Carine Wouters, Katrien Lagrou, Sabine Tejpar, Stephanie Humblet-Baron, P. A. Penttila, Jonas Yserbyt, S. Rex, E. Pollet, Jan Gunst, F. De Smet, Y. Van Herck, Vanderbeke, L [0000-0002-3364-1213], Van Herck, Y [0000-0003-4604-8010], De Smet, F [0000-0002-6669-3335], Martinod, K [0000-0002-1026-6107], Arijs, I [0000-0002-9415-083X], Dauwe, D [0000-0002-9771-2543], Dreesen, E [0000-0002-0785-2930], Emmaneel, A [0000-0003-4569-2330], Gunst, J [0000-0003-2470-6393], Jansen, S [0000-0002-9344-131X], Liston, A [0000-0002-6272-4085], Mercier, T [0000-0002-1517-6426], Neyts, J [0000-0002-0033-7514], Panovska, D [0000-0003-0906-3860], Penttila, PA [0000-0002-5861-4430], Proost, P [0000-0002-0133-5545], Qian, J [0000-0001-6145-045X], Quintelier, K [0000-0001-5306-5615], Raes, J [0000-0002-1337-041X], Saeys, Y [0000-0002-0415-1506], Thevissen, K [0000-0003-0275-9072], Vandenhaute, J [0000-0001-9485-8806], Van Gassen, S [0000-0002-7119-5330], Vos, R [0000-0002-3468-9251], Garg, AD [0000-0002-9976-9922], Matthys, P [0000-0002-9685-6836], Lambrechts, D [0000-0002-3429-302X], Wauters, E [0000-0002-0115-0030], and Apollo - University of Cambridge Repository

Subjects
Oncology, Male, 0301 basic medicine, animal diseases, medicine.medical_treatment, General Physics and Astronomy, Disease, Extracellular Traps, Severity of Illness Index, Monocytes, Neutrophil Activation, 0302 clinical medicine, Informed consent, Immunopathology, Medicine and Health Sciences, Medicine, health care economics and organizations, Multidisciplinary, Middle Aged, Acquired immune system, Cytokine release syndrome, medicine.anatomical_structure, Cytokine, 030220 oncology & carcinogenesis, Cytokines, Female, Infection, Cytokine Release Syndrome, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Science, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Antigen-Presenting Cells, Article, General Biochemistry, Genetics and Molecular Biology, Immunophenotyping, 03 medical and health sciences, Immune system, Disease severity, Antigen, Internal medicine, Humans, Aged, SARS-CoV-2, business.industry, Monocyte, Histocompatibility Antigens Class II, COVID-19, Biology and Life Sciences, General Chemistry, Neutrophil extracellular traps, medicine.disease, 030104 developmental biology, Viral infection, Case-Control Studies, Immunology, CELLS, business, Cytokine storm
Abstract

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity., The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.

Published
2021

48. A Core Outcome Set for Inflammatory Bowel Diseases: Development and Recommendations for Implementation in Clinical Practice Through an International Multi-stakeholder Consensus Process.

Author

Fierens L, Carney N, Novacek G, van der Woude CJ, Siegmund B, Casellas F, Borruel N, Huberts AS, Sonnenberg E, Gerold N, Primas C, Hedin CRH, Stamm T, Julsgaard M, Fiorino G, Radice S, Zini MLL, Gross E, Sander C, Arijs I, Vakouftsi VR, Koltai T, Health Outcomes Observatory H O Patient Advisory Board For Inflammatory Bowel Diseases, Health Outcomes Observatory H O Steering Committee, Charlafti I, and Ferrante M

Subjects
Humans, Outcome Assessment, Health Care methods, Biomarkers blood, Biomarkers analysis, Patient Reported Outcome Measures, Leukocyte L1 Antigen Complex analysis, Stakeholder Participation, C-Reactive Protein analysis, Surveys and Questionnaires, Inflammatory Bowel Diseases therapy, Delphi Technique, Consensus
Abstract

Background and Aims: Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method., Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set., Results: In total, 136 stakeholders (45 IBD patients [advocates], 74 health care professionals/researchers, 13 industry representatives, and four regulators) from 20 different countries participated. The final set includes 18 case-mix variables, three biomarkers [haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation] for completeness, and 28 outcomes (including 16 patient-reported outcomes [PROs] and one patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form, to collect generic PROs annually., Conclusions: A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven, and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Published
2024
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49. Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.

Author

Venken T, Miller IS, Arijs I, Thomas V, Barat A, Betge J, Zhan T, Gaiser T, Ebert MP, O'Farrell AC, Prehn J, Klinger R, O'Connor DP, Moulton B, Murphy V, Serna G, Nuciforo PG, McDermott R, Bird B, Leonard G, Grogan L, Horgan A, Schulte N, Moehler M, Lambrechts D, and Byrne AT

Abstract

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment., (© 2024. The Author(s).)

Published
2024
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50. Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders.

Author

Matveeva A, Watters O, Rukhadze A, Khemka N, Gentile D, Perez IF, Llorente-Folch I, Farrell C, Lo Cacciato E, Jackson J, Piazzesi A, Wischhof L, Woods I, Halang L, Hogg M, Muñoz AG, Dillon ET, Matallanas D, Arijs I, Lambrechts D, Bano D, Connolly NMC, and Prehn JHM

Subjects
Mice, Animals, Humans, Proteomics, Mice, Transgenic, Gene Expression Profiling, RNA, Messenger, Frontotemporal Dementia metabolism, Amyotrophic Lateral Sclerosis pathology, Neurodegenerative Diseases, Pick Disease of the Brain, Mitochondrial Diseases
Abstract

Objective: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD., Methods: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage., Results: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology., Conclusions: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Published
2024
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