Background: Juvenile neuronal ceroid lipofuscinoses (JNCL) or juvenile Batten disease is a recessively inherited childhood neurodegenerative disorder resulting from a mutation in CLN3, which encodes a putative lysosomal protein of unknown function.
Aim: Recent evidence suggests that a disruption in CLN3 function results in altered regulation of arginine transport into lysosomes, and may influence intracellular arginine levels. We sought to investigate the possible consequences of arginine dysregulation in the brain of the Cln3(-/-) mouse model of JNCL.
Methods: Using a combination of enzyme assays, metabolite profiling, quantitative reverse-transcription polymerase chain reaction and Western blotting, we analysed the activities and expression of enzymes involved in arginine metabolism in the cerebral cortex and cerebellum of Cln3(-/-) mice over several developmental time points.
Results: We report subtle, but significant changes in the activities of enzymes involved in the citrulline-NO recycling pathway, and altered regulation of neuronal nitric oxide synthase in the cortex and cerebellum of Cln3(-/-) mice. In addition, a significant decrease in arginine transport into cerebellar granule cells was observed, despite an apparent upregulation of the cationic amino acid transporter-1 transporter at the cell surface. Our results provide further evidence that CLN3 function and arginine homeostasis are intricately related, and that cellular mechanisms may act to compensate for the loss of this protein.
Conclusions: This and other studies indicate that CLN3 dysfunction in JNCL may result in multiple disturbances in metabolism that together contribute to the pathophysiological processes underlying this disease.