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Sphingolipid metabolism modulates motor neuron degeneration in Drosophila

We are interested in the involvement of sphingolipids in neurodegeneration in Drosophila. To look at this, we study animals deficient in Blue cheese, a BEACH domain protein involved in autophagy and lysosomal transport, and highly expressed in the nervous system. Blue cheese mutants exhibit shortened life span, extensive neuronal loss and accumulation of ubiquitinated proteins in the brain (Finley et al, 2003). The role of BEACH domain in the FAN protein, which triggers neutral sphingomyelinase activity (Segui et al, 1999), and the involvement of sphingolipids in various human neurodegenerative conditions (Cutler et al, 2002, 2004; Han et al, 2004), led us to hypothesize that blue cheese mutation could lead to degeneration by altering sphingolipid balance. We introduced mutations in the sphingolipid‐biosynthetic pathway into the blue cheese background to look for modification of the phenotype (motorneuron count). Lace (SPT) and slab (CDase) mutants and overexpressors in the background of the blue cheese mutation indeed modulated neuronal survival, in a way that suggests that ceramide availability in the brain is critical. Mass spectrometric quantification of sphingolipid levels in mutant larval brains show dysregulation of ceramides and changes in activation of putative ceramide‐regulated MAPK signaling pathway targets P‐Akt, P‐JNK and P‐MKK4, which may affect neuronal survival. Based on these sphingolipid changes and genetic interactions, we propose a possible mechanism whereby blue cheese may regulate sphingomyelinase and SPT, and act synergistically with ceramidase.