{"entity": "researcher", "timestamp": "2026-08-13T18:17:29.882Z", "family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "affiliations": ["Department of Pharmacology and Clinical Neuroscience, Ume\u00e5 University, 90187 Ume\u00e5, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06"}}, "publications": [{"entity": "publication", "iuid": "98c3436054da482d8ed7c2c09222f5c2", "links": {"self": {"href": "https://publications.scilifelab.se/publication/98c3436054da482d8ed7c2c09222f5c2.json"}, "display": {"href": "https://publications.scilifelab.se/publication/98c3436054da482d8ed7c2c09222f5c2"}}, "title": "Extracellular Histones as Exosome Membrane Proteins Regulated by Cell Stress.", "authors": [{"family": "Singh", "given": "Birendra", "initials": "B"}, {"family": "Fredriksson Sundbom", "given": "Marcus", "initials": "M", "orcid": "0000-0002-3586-4197", "researcher": {"href": "https://publications.scilifelab.se/researcher/b9fb80c88da9467c9984f169cd3da016.json"}}, {"family": "Muthukrishnan", "given": "Uma", "initials": "U"}, {"family": "Natarajan", "given": "Balasubramanian", "initials": "B"}, {"family": "Stransky", "given": "Stephanie", "initials": "S"}, {"family": "G\u00f6rgens", "given": "Andr\u00e9", "initials": "A", "orcid": "0000-0001-9198-0857", "researcher": {"href": "https://publications.scilifelab.se/researcher/ea5f85e2c23a4515a39a2fa23d665a99.json"}}, {"family": "Nordin", "given": "Joel Z", "initials": "JZ", "orcid": "0000-0002-3653-7710", "researcher": {"href": "https://publications.scilifelab.se/researcher/37075c4179534fc8a927c4e1330e92c7.json"}}, {"family": "Wiklander", "given": "Oscar P B", "initials": "OPB"}, {"family": "Sandblad", "given": "Linda", "initials": "L"}, {"family": "Sidoli", "given": "Simone", "initials": "S"}, {"family": "El Andaloussi", "given": "Samir", "initials": "S"}, {"family": "Haney", "given": "Michael", "initials": "M", "orcid": "0000-0002-4049-8910", "researcher": {"href": "https://publications.scilifelab.se/researcher/837c6b12b0ad44f8b1e2a26cb7cd245b.json"}}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}], "type": "journal article", "published": "2025-02-00", "journal": {"title": "J Extracell Vesicles", "issn": "2001-3078", "volume": "14", "issue": "2", "pages": "e70042", "issn-l": "2001-3078"}, "abstract": "Histones are conserved nuclear proteins that function as part of the nucleosome in the regulation of chromatin structure and gene expression. Interestingly, extracellular histones populate biofluids from healthy individuals, and when elevated, may contribute to various acute and chronic diseases. It is generally assumed that most extracellular histones exist as nucleosomes, as components of extracellular chromatin. We analysed cell culture models under normal and stressed conditions to identify pathways of histone secretion. We report that core and linker histones localize to extracellular vesicles (EVs) and are secreted via the multivesicular body/exosome pathway. Upregulation of EV histone secretion occurs in response to cellular stress, with enhanced vesicle secretion and a shift towards a population of smaller EVs. Most histones were membrane associated with the outer surface of EVs. Degradation of EV-DNA did not impact significantly on EV-histone association. Individual histones and histone octamers bound strongly to liposomes and EVs, but nucleosomes did not, showing histones do not require DNA for EV binding. Histones colocalized to tetraspanin positive EVs but using genetic or pharmacological intervention, we found that all known pathways of exosome biogenesis acted positively on histone secretion. Inhibition of autophagy and lysosomal degradation had a strong positive effect on EV histone release. Unexpectedly, EV-associated histones lacked the extensive post-translational modification of their nuclear counterparts, suggesting loss of PTMs may be involved in their trafficking or secretion. Our data does not support a significant role for EV-histones existing as nucleosomes. We show for the first time that histones are secreted from cells as membrane proteins via EVs/exosomes. This fundamental discovery provides support for further investigation of the biological activity of exosome associated histones and their role in disease.", "doi": "10.1002/jev2.70042", "pmid": "39976275", "labels": {"Cryo-EM": "Collaborative", "Integrated Microscopy Technologies Ume\u00e5": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC11840699"}], "notes": [], "created": "2025-11-03T12:14:46.643Z", "modified": "2025-11-18T13:15:12.096Z"}, {"entity": "publication", "iuid": "2cd83bb48a16401c9977dbc5ffaf2627", "links": {"self": {"href": "https://publications.scilifelab.se/publication/2cd83bb48a16401c9977dbc5ffaf2627.json"}, "display": {"href": "https://publications.scilifelab.se/publication/2cd83bb48a16401c9977dbc5ffaf2627"}}, "title": "A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation.", "authors": [{"family": "Knyazeva", "given": "Anastasia", "initials": "A"}, {"family": "Li", "given": "Shuang", "initials": "S", "orcid": "0000-0001-7708-0166", "researcher": {"href": "https://publications.scilifelab.se/researcher/b0a0ec3547924f43854a957662cd5089.json"}}, {"family": "Corkery", "given": "Dale P", "initials": "DP", "orcid": "0000-0001-7930-0134", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e668ad5ea8458b8d0eebc3c653a62e.json"}}, {"family": "Shankar", "given": "Kasturika", "initials": "K", "orcid": "0000-0002-0011-3756", "researcher": {"href": "https://publications.scilifelab.se/researcher/4487e20554dc47688cd5d930c2ca1f74.json"}}, {"family": "Herzog", "given": "Laura K", "initials": "LK", "orcid": "0000-0002-3322-7864", "researcher": {"href": "https://publications.scilifelab.se/researcher/b1e8cfcb24a144d196251f02ab95db4d.json"}}, {"family": "Zhang", "given": "Xuepei", "initials": "X"}, {"family": "Singh", "given": "Birendra", "initials": "B", "orcid": "0000-0002-7246-1442", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a37eae28b0b45678502b7be34dbae99.json"}}, {"family": "Niggemeyer", "given": "Georg", "initials": "G"}, {"family": "Grill", "given": "David", "initials": "D"}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}, {"family": "Gaetani", "given": "Massimiliano", "initials": "M", "orcid": "0000-0001-5610-0797", "researcher": {"href": "https://publications.scilifelab.se/researcher/7b58e5cef5224fdcbdcd626fb798b169.json"}}, {"family": "Carlson", "given": "Lars-Anders", "initials": "LA", "orcid": "0000-0003-2342-6488", "researcher": {"href": "https://publications.scilifelab.se/researcher/ba0e366ce21e49b48212bbed5a0a7bd1.json"}}, {"family": "Waldmann", "given": "Herbert", "initials": "H", "orcid": "0000-0002-9606-7247", "researcher": {"href": "https://publications.scilifelab.se/researcher/54124c0b6aaa4711ab41a2492264fd9a.json"}}, {"family": "Wu", "given": "Yao-Wen", "initials": "YW", "orcid": "0000-0002-2573-8736", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7fe2a390f534022b4e9a85f986747c7.json"}}], "type": "journal article", "published": "2024-04-23", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "issn-l": "0027-8424", "volume": "121", "issue": "17", "pages": "e2317680121"}, "abstract": "The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.", "doi": "10.1073/pnas.2317680121", "pmid": "38635626", "labels": {"Chemical Proteomics": "Collaborative", "Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11047075"}], "notes": [], "created": "2024-07-25T13:10:40.169Z", "modified": "2024-11-27T11:33:55.833Z"}, {"entity": "publication", "iuid": "79c72c42ec3a4ac5a5ca948ca0fdc2ef", "links": {"self": {"href": "https://publications.scilifelab.se/publication/79c72c42ec3a4ac5a5ca948ca0fdc2ef.json"}, "display": {"href": "https://publications.scilifelab.se/publication/79c72c42ec3a4ac5a5ca948ca0fdc2ef"}}, "title": "Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans.", "authors": [{"family": "Pu", "given": "Longjun", "initials": "L"}, {"family": "Wang", "given": "Jing", "initials": "J"}, {"family": "Lu", "given": "Qiongxuan", "initials": "Q"}, {"family": "Nilsson", "given": "Lars", "initials": "L"}, {"family": "Philbrook", "given": "Alison", "initials": "A"}, {"family": "Pandey", "given": "Anjali", "initials": "A"}, {"family": "Zhao", "given": "Lina", "initials": "L"}, {"family": "Schendel", "given": "Robin van", "initials": "RV", "orcid": "0000-0001-7068-0679", "researcher": {"href": "https://publications.scilifelab.se/researcher/6aa5a36e5b534bab8a04b4c8f040abb4.json"}}, {"family": "Koh", "given": "Alan", "initials": "A", "orcid": "0000-0002-9267-455X", "researcher": {"href": "https://publications.scilifelab.se/researcher/af8b3e661b9247bd866018357cef9436.json"}}, {"family": "Peres", "given": "Tanara V", "initials": "TV", "orcid": "0000-0003-0199-8653", "researcher": {"href": "https://publications.scilifelab.se/researcher/3cb3594666cf4c298ca22e457ec20e28.json"}}, {"family": "Hashi", "given": "Weheliye H", "initials": "WH"}, {"family": "Myint", "given": "Si Lhyam", "initials": "SL"}, {"family": "Williams", "given": "Chloe", "initials": "C"}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}, {"family": "Wai", "given": "Sun Nyunt", "initials": "SN", "orcid": "0000-0003-4793-4671", "researcher": {"href": "https://publications.scilifelab.se/researcher/261986c5cf8f48878b74c4f60cc7af69.json"}}, {"family": "Brown", "given": "Andre", "initials": "A"}, {"family": "Tijsterman", "given": "Marcel", "initials": "M", "orcid": "0000-0001-8465-9002", "researcher": {"href": "https://publications.scilifelab.se/researcher/b1e816845f6048e2a2c7dc29e9a13cdf.json"}}, {"family": "Sengupta", "given": "Piali", "initials": "P", "orcid": "0000-0001-7468-0035", "researcher": {"href": "https://publications.scilifelab.se/researcher/244628c8890d4399a0a98fb0f8bc5ae7.json"}}, {"family": "Henriksson", "given": "Johan", "initials": "J", "orcid": "0000-0002-7745-2844", "researcher": {"href": "https://publications.scilifelab.se/researcher/44339821900646b3881d4b4dfd09e8d5.json"}}, {"family": "Chen", "given": "Changchun", "initials": "C", "orcid": "0000-0003-2233-8996", "researcher": {"href": "https://publications.scilifelab.se/researcher/4cfa009cd5bc4951bcf6d5f4265b2c68.json"}}], "type": "journal article", "published": "2023-12-18", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "14", "issue": "1", "pages": "8410", "issn-l": "2041-1723"}, "abstract": "G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.", "doi": "10.1038/s41467-023-44177-z", "pmid": "38110404", "labels": {"NGI Short read": "Service", "NGI Stockholm (Genomics Production)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10728192"}, {"db": "pii", "key": "10.1038/s41467-023-44177-z"}], "notes": [], "created": "2024-01-02T13:26:28.816Z", "modified": "2024-11-25T10:16:17.175Z"}, {"entity": "publication", "iuid": "73b9af32e38543cba8ac15a4d1d9f5e6", "links": {"self": {"href": "https://publications.scilifelab.se/publication/73b9af32e38543cba8ac15a4d1d9f5e6.json"}, "display": {"href": "https://publications.scilifelab.se/publication/73b9af32e38543cba8ac15a4d1d9f5e6"}}, "title": "Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes", "authors": [{"family": "Knyazeva", "given": "Anastasia", "initials": "A", "orcid": "0000-0001-8504-9126", "researcher": {"href": "https://publications.scilifelab.se/researcher/8a35aa837d114bbc9cab91622d1d7e13.json"}}, {"family": "Li", "given": "Shuang", "initials": "S"}, {"family": "Corkery", "given": "Dale P", "initials": "DP", "orcid": "0000-0001-7930-0134", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e668ad5ea8458b8d0eebc3c653a62e.json"}}, {"family": "Shankar", "given": "Kasturika", "initials": "K", "orcid": "0000-0002-0011-3756", "researcher": {"href": "https://publications.scilifelab.se/researcher/4487e20554dc47688cd5d930c2ca1f74.json"}}, {"family": "Herzog", "given": "Laura K", "initials": "LK", "orcid": "0000-0002-3322-7864", "researcher": {"href": "https://publications.scilifelab.se/researcher/b1e8cfcb24a144d196251f02ab95db4d.json"}}, {"family": "Zhang", "given": "Xuepei", "initials": "X", "orcid": "0000-0001-8304-8437", "researcher": {"href": "https://publications.scilifelab.se/researcher/c8a70e282ff2484d8acd3daa84c480b4.json"}}, {"family": "Singh", "given": "Birendra", "initials": "B", "orcid": "0000-0002-7246-1442", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a37eae28b0b45678502b7be34dbae99.json"}}, {"family": "Niggemeyer", "given": "Georg", "initials": "G"}, {"family": "Grill", "given": "David", "initials": "D"}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}, {"family": "Gaetani", "given": "Massimiliano", "initials": "M", "orcid": "0000-0001-5610-0797", "researcher": {"href": "https://publications.scilifelab.se/researcher/7b58e5cef5224fdcbdcd626fb798b169.json"}}, {"family": "Carlson", "given": "Lars Anders", "initials": "LA", "orcid": "0000-0003-2342-6488", "researcher": {"href": "https://publications.scilifelab.se/researcher/ba0e366ce21e49b48212bbed5a0a7bd1.json"}}, {"family": "Waldmann", "given": "Herbert", "initials": "H", "orcid": "0000-0002-9606-7247", "researcher": {"href": "https://publications.scilifelab.se/researcher/54124c0b6aaa4711ab41a2492264fd9a.json"}}, {"family": "Wu", "given": "Yao Wen", "initials": "YW", "orcid": "0000-0002-2573-8736", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7fe2a390f534022b4e9a85f986747c7.json"}}], "type": "posted-content", "published": "2023-08-28", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2023.08.28.555152", "pmid": null, "labels": {"Chemical Proteomics": "Collaborative"}, "xrefs": [], "notes": [], "created": "2023-12-11T16:34:09.210Z", "modified": "2025-12-18T19:46:51.120Z"}, {"entity": "publication", "iuid": "be135146fd7c406a88c1ff9664b6e423", "links": {"self": {"href": "https://publications.scilifelab.se/publication/be135146fd7c406a88c1ff9664b6e423.json"}, "display": {"href": "https://publications.scilifelab.se/publication/be135146fd7c406a88c1ff9664b6e423"}}, "title": "GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism.", "authors": [{"family": "Muthu", "given": "Magesh", "initials": "M"}, {"family": "Kumar", "given": "Ranjeet", "initials": "R"}, {"family": "Syed Khaja", "given": "Azharuddin Sajid", "initials": "AS", "orcid": "0000-0003-1594-1826", "researcher": {"href": "https://publications.scilifelab.se/researcher/aa3cc7ab186b447987513bbad0ab7d92.json"}}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}, {"family": "Persson", "given": "Jenny L", "initials": "JL"}, {"family": "Nordstr\u00f6m", "given": "Anders", "initials": "A", "orcid": "0000-0003-3676-817X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4b1803a3f7624f0d82abd552448bdaed.json"}}], "type": "journal article", "published": "2019-12-05", "journal": {"volume": "11", "issn": "2072-6694", "issue": "12", "pages": "1945", "title": "Cancers (Basel)", "issn-l": "2072-6694"}, "abstract": "Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 \u03bcM in resistant GLUL KO A549 cells compared to 28 \u03bcM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.", "doi": "10.3390/cancers11121945", "pmid": "31817360", "labels": {"Bioinformatics Support for Computational Resources": "Service", "Swedish Metabolomics Centre": "Service"}, "xrefs": [{"db": "pii", "key": "cancers11121945"}, {"db": "pmc", "key": "PMC6966511"}], "notes": [], "created": "2020-01-07T15:45:49.261Z", "modified": "2025-10-17T13:03:17.024Z"}, {"entity": "publication", "iuid": "ab001b78b5ef4dcf89e80acc67c003bf", "links": {"self": {"href": "https://publications.scilifelab.se/publication/ab001b78b5ef4dcf89e80acc67c003bf.json"}, "display": {"href": "https://publications.scilifelab.se/publication/ab001b78b5ef4dcf89e80acc67c003bf"}}, "title": "The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension.", "authors": [{"family": "Keskin", "given": "Isil", "initials": "I"}, {"family": "Forsgren", "given": "Elin", "initials": "E"}, {"family": "Lehmann", "given": "Manuela", "initials": "M"}, {"family": "Andersen", "given": "Peter M", "initials": "PM"}, {"family": "Br\u00e4nnstr\u00f6m", "given": "Thomas", "initials": "T"}, {"family": "Lange", "given": "Dale J", "initials": "DJ"}, {"family": "Synofzik", "given": "Matthis", "initials": "M"}, {"family": "Nordstr\u00f6m", "given": "Ulrika", "initials": "U"}, {"family": "Zetterstr\u00f6m", "given": "Per", "initials": "P"}, {"family": "Marklund", "given": "Stefan L", "initials": "SL"}, {"family": "Gilthorpe", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-6884-4774", "researcher": {"href": "https://publications.scilifelab.se/researcher/7eb2a4f38fdc4e0db2516a17d9abdf06.json"}}], "type": "journal article", "published": "2019-07-00", "journal": {"title": "Acta Neuropathol.", "issn": "1432-0533", "volume": "138", "issue": "1", "pages": "85-101", "issn-l": "0001-6322"}, "abstract": "Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O 2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low O2 tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.", "doi": "10.1007/s00401-019-01986-1", "pmid": "30863976", "labels": {"Swedish Metabolomics Centre": "Service"}, "xrefs": [{"db": "pii", "key": "10.1007/s00401-019-01986-1"}, {"db": "pmc", "key": "PMC6570705"}], "notes": [], "created": "2020-01-21T10:13:11.280Z", "modified": "2025-10-17T13:03:17.508Z"}]}