Transcriptional Feedback Links Lipid Synthesis to Synaptic Vesicle Pools in Drosophila Photoreceptors

Abstract

Neurons can maintain stable synaptic connections across adult life. However, the signals that regulate expression of synaptic proteins in the mature brain are incompletely understood. Here, we describe a transcriptional feedback loop between the biosynthesis and repertoire of specific phospholipids and the synaptic vesicle pool in adult Drosophila photoreceptors. Mutations that disrupt biosynthesis of a subset of phospholipids cause degeneration of the axon terminal and loss of synaptic vesicles. Although degeneration of the axon terminal is dependent on neural activity, activation of sterol regulatory element binding protein (SREBP) is both necessary and sufficient to cause synaptic vesicle loss. Our studies demonstrate that SREBP regulates synaptic vesicle levels by interacting with tetraspanins, critical organizers of membranous organelles. SREBP is an evolutionarily conserved regulator of lipid biosynthesis in non-neuronal cells; our studies reveal a surprising role for this feedback loop in maintaining synaptic vesicle pools in the adult brain.

An early endosome–derived retrograde trafficking pathway promotes secretory granule maturation

“…Tsp39D knockdown resulted in small SGs, yet this phenotype is not fully suppressed by expression of CD63-GFP, indicating that the role of Tsp39D in SG maturation is distinct from Tsp29Fa. On the other hand, Tsp39D expression is crucial for maintenance of synaptic vesicles in Drosophila photoreceptor cells (Tsai et al, 2019), suggesting that CD63 homologues might carry out analogous functions in regulated secretion in different tissues.…”

PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila

“…We next examined the morphology of the lamina cartridge, the organized synaptic modules where R1-R6 photoreceptors project axons to, in pect 29 flies. The structure of the lamina cartridge was intact and mitochondria were normal in pect 29 flies, although synaptic vesicles were disrupted ( Fig 5E ) [ 25 ]. We compared ATP levels between wild-type and pect 29 retinas to assess mitochondrial function and found similar ATP levels in pect 29 mutants and controls.…”

“…A recent study also identified recessive lethal mutations in pect and demonstrated that the biosynthesis of specific phospholipids is linked to neurodegeneration and synaptic vesicle loss in adult Drosophila photoreceptors [ 25 ]. In pect omb593 mutants levels of PE 34:1 and PE 36:2 were reduced, but the overall proportions of PE species were not significantly changed, whereas we detected a significant reduction in total cellular PE levels.…”

“…Thus PECT H55Y might reduce PE levels to a much lesser extent than complete loss of pect , and this cellular PE reduction could be compensated by the alternative PSD pathway. Moreover, knocking down srebp (regulatory element binding protein) reversed the loss of synaptic vesicles, but failed to suppress axonal or retinal degeneration in pect omb593 mutants [ 25 ]. Therefore, SREBP is a downstream factor of PE deficiency and specifically functions in maintaining the synaptic vesicle pools.…”

“…The Drosophila visual system is a powerful genetic model for dissecting the mechanisms of neuronal function and related neurodegenerative diseases [ 23 , 24 ]. In Drosophila photoreceptor neurons, knocking down the PSD pathway results in neurodegeneration, and disrupting the CDP-ethanolamine pathway leads to the loss of synaptic vesicles [ 25 , 26 ]. In the present study, we conducted a forward genetic screen in Drosophila to identify genes required for photoreceptor survival and isolated loss-of-function mutations in the gene pect , which encodes phosphoethanolamine cytidylyltransferase .…”