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

Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients. Neurobiol Dis. 2020 Jul 31;:105025 Authors: Chen Q, Konrad C, Sandhu D, Roychoudhury D, Schwartz BI, Cheng RR, Bredvik K, Kawamata H, Calder EL, Studer L, Fischer SM, Manfredi G, Gross SS 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 diffe...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research