Glycosphingolipids linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick Type C.

The lipid storage disease Niemann Pick Type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employ a Drosophila model to test links between glycosphingolipids, neurotransmission, and neurodegeneration. We find npc1a nulls have elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which is phenocopied in brainiac (brn) mutants impairing mannosylglucosylceramide (MacCer) glycosylation. npc1a;brn double mutants have the same elevated synaptic transmission, suggesting npc1a and brn function within the same pathway. Glucosylceramide (GlcCer) synthase inhibition with miglustat prevents elevated neurotransmission in npc1a and brn mutants, further suggesting epistasis. Synaptic MacCer does not accumulate in the NPC model, but GlcCer levels are increased, suggesting GlcCer is responsible for the elevated synaptic transmission. Null npc1a mutants have heightened neurodegeneration, but no significant motor neuron or glial cell death, indicating dying cells are interneurons and that elevated neurotransmission precedes neurodegeneration. Glycosphingolipid synthesis mutants also have greatly heightened neurodegeneration, with similar neurodegeneration in npc1a;brn double mutants, again suggesting that npc1a and brn function in the same pathway. These findings indicate causal links between glycosphingolipid-dependent neurotransmission and neurodegeneration in this NPC disease model.