Deletion of btn1, an orthologue of CLN3, increases glycolysis and perturbs amino acid metabolism in the fission yeast model of Batten disease

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of autosomal recessive neurodegenerative diseases affecting children. To date, the disease pathogenesis remains unknown, although the role of lysosomal impairment is widely recognized across the different diseases. Recently, the creation of simple models of juvenile NCL (Batten disease) has provided additional insights into the disease mechanism at the molecular level. We report defects in metabolism identified in the Schizosacchromyces pombe yeast model, where btn 1, the orthologue of CLN 3, has been deleted, using a metabolomics approach based on high resolution 1 H and 13 C NMR spectroscopy. Such changes represent the first documented metabolic changes associated with deletion of btn 1. A decrease in extracellular glucose and increases in the concentration of extracellular ethanol and alanine labelling demonstrate increased glycolytic flux that may arise from vacuolar impairment, whilst amino acid changes were detected which were also in accordance with defective vacuolar functionality. That these changes were detected using a metabolomic based approach advocates its use to further analyse other yeast models of human disease to better understand the function of orthologue genes. NMR spectroscopy based metabolomics has been used to investigate the phenotype of a yeast model of Batten disease, demonstrating altered glycolytic rate which has implications for our understanding of the human disease.