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

• Published in: Genetics (Austin) 2023-04, Vol.223 (4)
• Main Authors: Sidisky, Jessica M, de Paula Moreira, Danielle, Okumus, Meryem, Caratenuto, Russell, Drost, Cassidy, Connors, Bali, Hussain, Sarrah, Alkhatib, Stephanie, Babcock, Daniel T
• Format: Article
• Language: English
• Subjects: Aging; Animals; Drosophila; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Flight; Flight behavior; Fruit flies; Gene expression; Genes; Genetic screening; Genomes; Glial cells; Humans; Insects; Investigation; Maintenance; Motor neurons; Muscles; Nervous system; Neuroglia - metabolism; Neuromuscular Junction - metabolism; Neuromuscular junctions; Neuronal-glial interactions; Nucleotides; RNA-mediated interference; Single-nucleotide polymorphism; Structural integrity; Structure-function relationships; Synapses; Synapses - metabolism; Synaptic Transmission - genetics; Synaptogenesis
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1093/genetics/iyad025

Abstract 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.