Automated in vivo drug screen in zebrafish identifies synapse-stabilising drugs with relevance to spinal muscular atrophy

Ana-maria Oprişoreanu, Hannah L. Smith, Sophia Krix, Helena Chaytow, Neil O. Carragher, Thomas H. Gillingwater, Catherina G. Becker, Thomas Becker

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 a mutant for the axonal C-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 most-effective 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 platform can be used for drug and genetic screens, with wider relevance to synapse formation and stabilisation.
Original languageEnglish
JournalDisease Models and Mechanisms
Issue number4
Early online date26 Apr 2021
Publication statusE-pub ahead of print - 26 Apr 2021

Keywords / Materials (for Non-textual outputs)

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


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