Developmental Comparison of Ceramide in Wild-Type and Cln3^Δ/ Mouse Brains and Sera.

CLN3 disease is a neurodevelopmental disease leading to early visual failure, motor decline, and death. CLN3 pathogenesis has been linked to dysregulation of ceramide, a key intracellular messenger impacting various biological functions. Ceramide is upregulated in brains of CLN3 patients and activates apoptosis. Ceramide levels over the lifespan of WT and Cln3^Δ mice were measured using the DGK assay. Ceramide subspecies were determined by LC-MS. Ceramide synthesis enzymes and pre- and post-synaptic mRNA expression was measured in Cln3^Δ and normal mouse brains. Neuronal cell death was established by cleavage and Caspases 3/6/9 and cytochrome C mRNA expression in Cln3^Δ and normal mouse brains. In WT mouse, a ceramide peak was noted at 3 weeks of age. The absence of this peak in Cln3^Δ mice might be related to early disease pathogenesis. Increase of ceramide in Cln3^Δ mouse brain at 24 weeks of age precedes neuronal apoptosis. The correlation between serum and brain ceramide in WT mice, and dysregulation of ceramide in serum and brain of Cln3^Δ mice, and the significant increase in ceramide in Cln3^Δ mouse brains and sera argue for use of easily accessible serum ceramide levels to track response to novel therapies in human CLN3 disease.

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