Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients.
| Publication Type | Academic Article |
| Authors | Chen Q, Konrad C, Sandhu D, Roychoudhury D, Schwartz B, Cheng R, Bredvik K, Kawamata H, Calder E, Studer L, Fischer S, Manfredi G, Gross S |
| Journal | Neurobiol Dis |
| Volume | 144 |
| Pagination | 105025 |
| Date Published | 08/01/2020 |
| ISSN | 1095-953X |
| Keywords | Amyotrophic Lateral Sclerosis, Cysteine, Fibroblasts, Glucose, Glutathione, Metabolome |
| 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. |
| DOI | 10.1016/j.nbd.2020.105025 |
| PubMed ID | 32745521 |
| PubMed Central ID | PMC7491150 |