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

Neurobiology of Disease

Steven.S. Gross¹  Steven.M. Fischer²  Dipa Roychoudhury²  Giovanni Manfredi³  Kirsten Bredvik³  Hibiki Kawamata³  Csaba Konrad³  Benjamin I. Schwartz⁴  Roger R. Cheng⁴  Qiuying Chen⁴  Davinder Sandhu⁴  Elizabeth L. Calder⁵  Lorenz Studer⁵ 

[1] Corresponding authors.;Agilent Technologies, Santa Clara, CA, USA;Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA;Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA;The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Center, New York, NY, USA;

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

DOI  :  

来源: DOAJ

【 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 ~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.

【 授权许可】

Unknown