Lafora Disease: Differential Metabolic Disturbances in Neurons and Astrocytes

Abstract

The brain is an incredible energy‐demanding organ and even small disturbances in brain energetics may have fatal consequences. Lafora disease (LD) is a rare metabolic and neurodegenerative disorder clinically presenting with tonic‐clonic epileptic seizures and myoclonic jerks. LD patients experience rapid neurodegeneration starting in early adolescence and the disease is indisputable fatal typically within 10 years of onset. LD is caused by mutations in the genes EPM2A or EPM2B encoding the proteins Laforin and Malin, both implicated in glycogen metabolism. However, the mechanism of disease is poorly understood, though emerging evidence suggests that neurons and glial cells are affected differently in LD. This study aims to elucidate the effect of laforin on central carbon metabolism in different cellular compartments. We employed a systematic characterization of glucose metabolism in cerebral brain slices from 3‐months old Epm2a−/− and wildtype animals in addition to primary cultures of neurons and astrocytes utilizing [U‐13C]glucose and subsequent analysis by gas chromatography‐mass spectroscopy. Furthermore, slices were incubated with [U‐13C]glutamine and [U‐13C]glutamate to assess neuronal and astrocytic metabolic compartmentation, since glutamine is predominantly taken up and metabolized by neurons, and glutamate by astrocytes. The results of this study revealed complex disturbances of central carbon metabolism in the LD brain with clear metabolic distinctions between cerebral cell types. Disturbed oxidative glucose metabolism was observed in both primary cultures of neurons and astrocytes and in acutely isolated brain slices. Interestingly, the results indicate a compartmentalized glucose metabolism where neuronal glucose metabolism is downregulated, and astrocytic glucose metabolism upregulated in Epm2A−/− mice. Furthermore, neuronal glutamine metabolism was increased whereas glial glutamate metabolism was unaffected. Overall, this study provides evidence of altered glucose and neurotransmitter metabolism in LD related to loss of laforin and hereby dysfunctional glycogen metabolism. Further investigation of metabolic alterations in cerebral cell types may provide important insights into the mechanism of disease and targeted treatment.