High-throughput behavioral screen in C. elegans reveals Parkinson's disease drug candidates

Commun Biol. 2021 Feb 15;4(1):203. doi: 10.1038/s42003-021-01731-z.

Abstract

We recently linked branched-chain amino acid transferase 1 (BCAT1) dysfunction with the movement disorder Parkinson's disease (PD), and found that RNAi-mediated knockdown of neuronal bcat-1 in C. elegans causes abnormal spasm-like 'curling' behavior with age. Here we report the development of a machine learning-based workflow and its application to the discovery of potentially new therapeutics for PD. In addition to simplifying quantification and maintaining a low data overhead, our simple segment-train-quantify platform enables fully automated scoring of image stills upon training of a convolutional neural network. We have trained a highly reliable neural network for the detection and classification of worm postures in order to carry out high-throughput curling analysis without the need for user intervention or post-inspection. In a proof-of-concept screen of 50 FDA-approved drugs, enasidenib, ethosuximide, metformin, and nitisinone were identified as candidates for potential late-in-life intervention in PD. These findings point to the utility of our high-throughput platform for automated scoring of worm postures and in particular, the discovery of potential candidate treatments for PD.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Drug Repositioning*
  • High-Throughput Screening Assays*
  • Image Interpretation, Computer-Assisted
  • Machine Learning
  • Neural Networks, Computer
  • Posture*
  • Proof of Concept Study
  • RNA Interference
  • Transaminases / genetics
  • Transaminases / metabolism
  • Workflow

Substances

  • Antiparkinson Agents
  • Caenorhabditis elegans Proteins
  • bcat-1 protein, C elegans
  • Transaminases