Cover Story Current Issue

Altered amino acid metabolism is increasingly appreciated as a key driver in the pathology of multiple diseases, including metabolic syndrome, cancer, and neurological disease. Sphingolipids (SLs) are synthesized from serine and fatty acyl-CoAs by serine palmitoyltransferase (SPT) and are critical signaling molecules and membrane components that are enriched in the nervous system and retina. When serine levels are low, alanine (or glycine) is used as a substrate by SPT to yield non-canonical 1-deoxysphingolipids (doxSLs) that drive neuropathy and cellular dysfunction through diverse mechanisms. This highlights a potential mechanism for crosstalk between amino acid metabolism and SL biosynthesis in the context of neurological dysfunction. Numerous heritable neurological and retinal disorders are causative or linked to mutations in genes encoding SL-metabolizing enzymes, including amyotrophic lateral sclerosis (ALS), Tay-Sachs, Niemann-Pick disease, Gaucher disease, Macular telangiectasia type II (MacTel), and hereditary sensory and autonomic neuropathy type 1 (HSAN1).

Courtney R. Green, Roberto Bonelli, Brendan R.E. Ansell, Simone Tzaridis, ... Marin L. Gantner

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Current Issue

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

Objectives

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 investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival.

Methods

We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene.

Results

We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after 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.

Conclusions

We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

Articles in Press

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B. Belton, Ram P. Chakrabarty, ... Robert G. Kalb

Objectives

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 investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival.

Methods

We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene.

Results

We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after 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.

Conclusions

We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

2021 impact factor: 8.568

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