Neurons undergo pathogenic metabolic reprograming in models of familial ALS

Abstract

Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis, ALS), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We find in our rodent models of familial ALS (fALS), impairment in neuronal glycolytic flux with maintained or enhanced activity of the citric acid cycle. This rewiring of metabolism is associated with normal ATP levels and redox status, supporting the notion that mitochondrial function is not compromised in neurons expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated mitochondrial dysfunction in a baleful manner and targeting this process can be healthful.