Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients

NEUROBIOLOGY OF DISEASE

卷:144

Article

Chen, Qiuying¹  Konrad, Csaba²  Sandhu, Davinder¹  Roychoudhury, Dipa³  Schwartz, Benjamin I.¹  Cheng, Roger R.¹  Bredvik, Kirsten²  Kawamata, Hibiki²  Calder, Elizabeth L.⁴  Studer, Lorenz⁴  Fischer, Steven. M.³  Manfredi, Giovanni²  Gross, Steven. S.¹ 

[1] Weill Cornell Med, Dept Pharmacol, New York, NY 10065 USA

[2] Brain & Mind Res Inst, Weill Cornell Med, New York, NY 10065 USA

[3] Agilent Technol, Santa Clara, CA USA

[4] Sloan Kettering Inst Canc Ctr, Ctr Stem Cell Biol, New York, NY USA

关键词: Sporadic amyotrophic lateral sclerosis;    Metabolomics;    Stable isotope tracing;    Transsulfuration;    Cysteine;    Methionine;    Disease stratification;   

DOI  :  10.1016/j.nbd.2020.105025

来源: Elsevier

【 摘 要 】

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 similar to 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-C-13]-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.