1. Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients
- Author
-
Qiuying Chen, Csaba Konrad, Davinder Sandhu, Dipa Roychoudhury, Benjamin I. Schwartz, Roger R. Cheng, Kirsten Bredvik, Hibiki Kawamata, Elizabeth L. Calder, Lorenz Studer, Steven.M. Fischer, Giovanni Manfredi, and Steven.S. Gross
- Subjects
Sporadic amyotrophic lateral sclerosis ,Metabolomics ,Stable isotope tracing ,Transsulfuration ,Cysteine ,Methionine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - 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.
- Published
- 2020
- Full Text
- View/download PDF