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

A. Ashleigh Long, Cecon T. Mahapatra, Elvin A. Woodruff, Jeff Rohrbough, Hung Tat Leung, Shikoh Shino, Lingling An, Rebecca W. Doerge, Mark M. Metzstein, William L. Pak, Kendal Broadie

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3303-3315
Number of pages13
JournalJournal of Cell Science
Volume123
Issue number19
DOIs
StatePublished - Oct 1 2010

Keywords

  • Drosophila
  • NMD pathway
  • Neurotransmission
  • Photoreceptor
  • Smg1
  • Synapse
  • Synaptic vesicle cycle
  • mRNA regulation

ASJC Scopus subject areas

  • Cell Biology

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