Integrated longitudinal metabolome and proteome analysis provides new insights into metabolic dysregulations in amyotrophic lateral sclerosis

Abstract

Abstract Background Amyotrophic lateral sclerosis (ALS) is an irreversible fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Due to the highly heterogeneous and complex pathophysiology of the disease, there is currently no effective treatment to retard the disease progression. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. Methods Here, we applied unbiased LC-MS-based metabolomics to plasma, lumbar spinal cord, and motor cortex tissues from SOD1G93A mice and wildtype (WT) littermates at different stages to explore the metabolic disturbance during disease progression. To elucidate the regulatory network underlying metabolic changes, spinal cords from SOD1G93A and WT mice in the symptomatic stage were further analyzed by proteomics. Results The results show that SOD1G93A mice presented marked dysregulations of lipid and purine metabolism in both plasma and spinal cord from the pre-symptomatic stage. Furthermore, the metabolic abnormalities were much more pronounced in the symptomatic stage. By integrating metabolomics and proteomics data, we demonstrated the importance of metabolic pathways in the tricarboxylic acid (TCA) cycle, arginine and proline metabolism, and fatty acid degradation in the progression of ALS pathophysiology. Conclusions Notably, for the first time, we highlighted that metabolic dysregulation in purine metabolism might be a critical event in the preclinical phase of ALS. The identified differential metabolites and proteins in our study complement existing data on metabolic reprogramming in ALS; the results from the integrative analysis might provide novel perspectives for early diagnosis and therapeutic intervention of the disease.