Automated in vivo drug screen in zebrafish identifies synapsestabilising drugs with relevance to spinal muscular atrophy

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ana Maria Oprişoreanu - , University of Edinburgh (Author)
  • Hannah L. Smith - , University of Edinburgh (Author)
  • Sophia Krix - , University of Edinburgh (Author)
  • Helena Chaytow - , University of Edinburgh (Author)
  • Neil O. Carragher - , University of Edinburgh (Author)
  • Thomas H. Gillingwater - , University of Edinburgh (Author)
  • Catherina G. Becker - , University of Edinburgh (Author)
  • Thomas Becker - , University of Edinburgh (Author)

Abstract

Synapses are particularly vulnerable in many neurodegenerative diseases and often the first to degenerate, for example in the motor neuron disease spinal muscular atrophy (SMA). Compounds that can counteract synaptic destabilisation are rare. Here, we describe an automated screening paradigm in zebrafish for small-molecule compounds that stabilize the neuromuscular synapse in vivo. We make use of amutant for the axonalC-type lectin chondrolectin (chodl), one of the main genes dysregulated in SMA. In chodl-/- mutants, neuromuscular synapses that are formed at the first synaptic site by growing axons are not fully mature, causing axons to stall, thereby impeding further axon growth beyond that synaptic site. This makes axon length a convenient read-out for synapse stability. We screened 982 small-molecule compounds in chodl chodl-/- mutants and found four that strongly rescued motor axon length. Aberrant presynaptic neuromuscular synapse morphology was also corrected. The mosteffective compound, the adenosine uptake inhibitor drug dipyridamole, also rescued axon growth defects in the UBA1-dependent zebrafish model of SMA. Hence, we describe an automated screening pipeline that can detect compounds with relevance to SMA. This versatile platformcan be used for drug and genetic screens,with wider relevance to synapse formation and stabilisation.

Details

Original languageEnglish
Article numberdmm.047761
JournalDMM Disease Models and Mechanisms
Volume14
Issue number4
Publication statusPublished - Apr 2021
Peer-reviewedYes
Externally publishedYes

External IDs

PubMed 33973627

Keywords

Keywords

  • Chondrolectin, Drug discovery, Phenotypic screening, Synapse stabilization, VAST, Zebrafish