4.6 Article

Impaired Pentose Phosphate Pathway in the Spinal Cord of the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Journal

MOLECULAR NEUROBIOLOGY
Volume 56, Issue 8, Pages 5844-5855

Publisher

SPRINGER
DOI: 10.1007/s12035-019-1485-6

Keywords

Energy metabolism; Glycolysis; Liquid chromatography-tandem mass spectrometry; Motor neuron disease; Pentose phosphate pathway; TCA cycle

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Funding

  1. Motor Neurone Disease Research Institute Australia [GIA 1704]

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Impairments in energy metabolism in amyotrophic lateral sclerosis (ALS) have long been known. However, the changes in the energy-producing pathways in ALS are not comprehensively understood. To investigate specific alterations in glucose metabolism in glycolytic, pentose phosphate, and TCA cycle pathways, we injected uniformly labeled [U-C-13]glucose to wild-type and hSOD1(G93A) mice at symptom onset (80days). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), levels of metabolites were determined in extracts of the cortex and spinal cord. In addition, the activities of several enzymes involved in glucose metabolism were quantified. In the spinal cord, the levels of pentose phosphate pathway (PPP) intermediate ribose 5-phosphate (p=0.037) were reduced by 37% in hSOD1(G93A) mice, while the % C-13 enrichments in glucose 6-phosphate were increased threefold. The maximal activities of the enzyme glucose 6-phosphate dehydrogenase were decreased by 24% in the spinal cord (p=0.005), suggesting perturbations in the PPP. The total amount of pyruvate in the cortex (p=0.039) was reduced by 20% in hSOD1(G93A) mice. Also, the activities of the glycolytic enzyme pyruvate kinase were reduced in the cortex by 31% (p=0.002), indicating alterations in glycolysis. No significant differences were seen in the total amounts as well as % C-13 enrichments in most TCA cycle intermediates, suggesting largely normal TCA cycle function. On the other hand, oxoglutarate dehydrogenase activity was decreased in the cortex, which may indicate increased oxidative stress. Overall, this study revealed decreased activity of the PPP in the spinal cord and alterations in glycolysis in hSOD1(G93A) mouse CNS tissues at the early symptomatic stage of disease.

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