{"doi":"10.1016/j.nbd.2020.105025","title":"Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients","abstract":"Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) and patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts and 43-controls, we found ~25% of sALS cases (termed sALS-1) are characterized by transsulfuration pathway upregulation, where methionine-derived-homocysteine is channeled into cysteine for glutathione synthesis. sALS-1 fibroblasts selectively exhibited a growth defect under oxidative conditions, fully-rescued by N-acetylcysteine (NAC). [U13C]-glucose tracing showed transsulfuration pathway activation with accelerated glucose flux into the Krebs cycle. We established a four-metabolite support vector machine model predicting sALS-1 metabotype with 97.5% accuracy. Both sALS-1 metabotype and growth phenotype were validated in an independent cohort of sALS cases. Importantly, plasma metabolite profiling identified a system-wide cysteine metabolism perturbation as a hallmark of sALS-1. Findings reveal that sALS patients can be stratified into distinct metabotypes with differential sensitivity to metabolic stress, providing novel insights for personalized therapy.","journal":"Neurobiology of Disease","year":2020,"id":72956,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":368948,"name":"Csaba Konràd","orcid":"0000-0002-1157-4574","position":1,"is_corresponding":false},{"id":384599,"name":"Davinder Sandhu","orcid":null,"position":2,"is_corresponding":false},{"id":384600,"name":"Dipa Roychoudhury","orcid":null,"position":3,"is_corresponding":false},{"id":384601,"name":"Benjamin I. Schwartz","orcid":null,"position":4,"is_corresponding":false},{"id":384602,"name":"Roger R. Cheng","orcid":null,"position":5,"is_corresponding":false},{"id":383950,"name":"Kirsten Bredvik","orcid":"0000-0003-4613-4808","position":6,"is_corresponding":false},{"id":383951,"name":"Hibiki Kawamata","orcid":"0000-0003-0020-6933","position":7,"is_corresponding":false},{"id":384603,"name":"Elizabeth L. Calder","orcid":null,"position":8,"is_corresponding":false},{"id":109231,"name":"Lorenz Studer","orcid":"0000-0003-0741-7987","position":9,"is_corresponding":false},{"id":384604,"name":"Steven M. Fischer","orcid":null,"position":10,"is_corresponding":false},{"id":368949,"name":"Giovanni Manfredi","orcid":"0000-0003-3893-1348","position":11,"is_corresponding":false},{"id":259684,"name":"Steven S. Gross","orcid":"0000-0001-8029-2338","position":12,"is_corresponding":false},{"id":259681,"name":"Qiuying Chen","orcid":"0000-0001-5909-3959","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T21:45:09.279825Z","pmid":"32745521","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}