Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients Journal Article
| Authors: | Chen, Q.; Konrad, C.; Sandhu, D.; Roychoudhury, D.; Schwartz, B. I.; Cheng, R. R.; Bredvik, K.; Kawamata, H.; Calder, E. L.; Studer, L.; Fischer, S. M.; Manfredi, G.; Gross, S. S. |
| Article 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). [U–13C]-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. © 2020 The Authors |
| Keywords: | adult; controlled study; middle aged; human cell; major clinical study; cohort analysis; prediction; fibroblast; upregulation; oxidative stress; homocysteine; glucose transport; methionine; cysteine; metabolic regulation; personalized medicine; citric acid cycle; metabolomics; carbon 13; amyotrophic lateral sclerosis; acetylcysteine; metabolic stress; human; male; female; priority journal; article; glutathione metabolism; transsulfuration; disease stratification; sporadic amyotrophic lateral sclerosis; stable isotope tracing; transsulfuration pathway |
| Journal Title: | Neurobiology of Disease |
| Volume: | 144 |
| ISSN: | 0969-9961 |
| Publisher: | Academic Press |
| Date Published: | 2020-10-01 |
| Start Page: | 105025 |
| Language: | English |
| DOI: | 10.1016/j.nbd.2020.105025 |
| PUBMED: | 32745521 |
| PROVIDER: | scopus |
| PMCID: | PMC7491150 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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