The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy.

Long AA, Mahapatra CT, Woodruff EA, Rohrbough J, Leung HT, Shino S, An L, Doerge RW, Metzstein MM, Pak WL, Broadie K
J Cell Sci. 2010 123 (Pt 19): 3303-15

PMID: 20826458 · PMCID: PMC2939802 · DOI:10.1242/jcs.069468

A systematic Drosophila forward genetic screen for photoreceptor synaptic transmission mutants identified no-on-and-no-off transient C (nonC) based on loss of retinal synaptic responses to light stimulation. The cloned gene encodes phosphatidylinositol-3-kinase-like kinase (PIKK) Smg1, a regulatory kinase of the nonsense-mediated decay (NMD) pathway. The Smg proteins act in an mRNA quality control surveillance mechanism to selectively degrade transcripts containing premature stop codons, thereby preventing the translation of truncated proteins with dominant-negative or deleterious gain-of-function activities. At the neuromuscular junction (NMJ) synapse, an extended allelic series of Smg1 mutants show impaired structural architecture, with decreased terminal arbor size, branching and synaptic bouton number. Functionally, loss of Smg1 results in a ~50% reduction in basal neurotransmission strength, as well as progressive transmission fatigue and greatly impaired synaptic vesicle recycling during high-frequency stimulation. Mutation of other NMD pathways genes (Upf2 and Smg6) similarly impairs neurotransmission and synaptic vesicle cycling. These findings suggest that the NMD pathway acts to regulate proper mRNA translation to safeguard synapse morphology and maintain the efficacy of synaptic function.

MeSH Terms (15)

Animals Drosophila Drosophila Proteins Genetic Complementation Test Genetic Testing Light Signal Transduction Morphogenesis Neuromuscular Junction Photoreceptor Cells, Invertebrate Presynaptic Terminals Protein-Serine-Threonine Kinases Retina Sequence Deletion Synaptic Transmission Synaptic Vesicles

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