PUBLICATION

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

Authors
Oprişoreanu, A.M., Smith, H.L., Krix, S., Chaytow, H., Carragher, N.O., Gillingwater, T.H., Becker, C.G., Becker, T.
ID
ZDB-PUB-210512-9
Date
2021
Source
Disease models & mechanisms   14(4): (Journal)
Registered Authors
Becker, Catherina G., Becker, Thomas
Keywords
Chondrolectin, Drug discovery, Phenotypic screening, Synapse stabilization, VAST, Zebrafish
MeSH Terms
  • Animals
  • Automation
  • Axons/drug effects
  • Axons/metabolism
  • Dipyridamole/pharmacology
  • Disease Models, Animal
  • Drug Evaluation, Preclinical*
  • Genetic Testing
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy, Spinal/pathology*
  • Mutation/genetics
  • Phenotype
  • Presynaptic Terminals/pathology
  • Small Molecule Libraries/pharmacology
  • Synapses/pathology*
  • Zebrafish/genetics
  • Zebrafish/physiology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
33973627 Full text @ Dis. Model. Mech.
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 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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes