Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila.

Maintaining synaptic communication is required to preserve nervous system function as an organism ages. While much work has been accomplished to understand synapse formation and development, we understand relatively little regarding maintaining synaptic integrity throughout aging. To better understand the mechanisms responsible for maintaining synaptic structure and function, we performed an unbiased forward genetic screen to identify genes required for synapse maintenance of adult Drosophila neuromuscular junctions. Using flight behavior as a screening tool, we evaluated flight ability in 198 lines from the Drosophila Genetic Reference Panel to identify single nucleotide polymorphisms (SNPs) that are associated with a progressive loss of flight ability with age. Among the many candidate genes identified from this screen, we focus here on 10 genes with clear human homologs harboring SNPs that are most highly associated with synaptic maintenance. Functional validation of these genes using mutant alleles revealed a progressive loss of synaptic structural integrity. Tissue-specific knockdown of these genes using RNA interference (RNAi) uncovered important roles for these genes in either presynaptic motor neurons, postsynaptic muscles, or associated glial cells, highlighting the importance of each component of tripartite synapses. These results offer greater insight into the mechanisms responsible for maintaining structural and functional integrity of synapses with age.

Mayday sustains trans-synaptic BMP signaling required for synaptic maintenance with age.

Maintaining synaptic structure and function over time is vital for overall nervous system function and survival. The processes that underly synaptic development are well understood. However, the mechanisms responsible for sustaining synapses throughout the lifespan of an organism are poorly understood. Here, we demonstrate that a previously uncharacterized gene, CG31475, regulates synaptic maintenance in adult Drosophila NMJs. We named CG31475 mayday due to the progressive loss of flight ability and synapse architecture with age. Mayday is functionally homologous to the human protein Cab45, which sorts secretory cargo from the Trans Golgi Network (TGN). We find that Mayday is required to maintain trans-synaptic BMP signaling at adult NMJs in order to sustain proper synaptic structure and function. Finally, we show that mutations in mayday result in the loss of both presynaptic motor neurons as well as postsynaptic muscles, highlighting the importance of maintaining synaptic integrity for cell viability.