Glial expression of Swiss-Cheese (SWS), the Drosophila orthologue of Neuropathy Target Esterase, is required for neuronal ensheathment and function

Swiss-cheese (SWS) and its vertebrate ortholog Neuropathy Target Esterase (NTE) cause progressive neuronal degeneration in Drosophila and mice and a complex syndrome in humans that includes mental retardation, spastic paraplegia, and blindness. SWS and NTE are widely expressed in neurons but can also be found in glia however the function in glia was unknown. We have used a knockdown approach to specifically address SWS function in glia and to probe for resulting neuronal dysfunctions. This revealed that loss of SWS in pseudocartridge glia causes the formation of multi-layered glial whorls in the lamina cortex, the first optic neuropil. This phenotype can be rescued by the expression of SWS and NTE suggesting that the glial function is conserved in the vertebrate protein. SWS is also required for the glial wrapping of neurons by ensheathing glia and its loss in glia causes axonal damage. We also detected severe locomotion deficits in glial SWS knockdown flies that already occurred at 2d and increased further with age. Utilizing the giant fiber system to test for underlying functional neuronal defects showed that the response latency to a stimulus was unchanged in knockdown flies compared to controls but the reliability with which the neurons responded to increasing frequencies was reduced. This shows that the loss of SWS in glia impairs neuronal function, thereby playing an important role in the phenotypes described in the sws mutant. It is therefore likely that changes in glia also contribute to the pathology observed in patients that carry mutations in NTE. D is ea se M o de ls & M ec ha ni sm s • D M M • A dv an ce a rt ic le