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

TitleHigh-throughput behavioral screen in C. elegans reveals Parkinson's disease drug candidates.
Publication TypeJournal Article
Year of Publication2021
AuthorsSohrabi, S, Mor, DE, Kaletsky, R, Keyes, W, Murphy, CT
JournalCommun Biol
Volume4
Issue1
Pagination203
Date Published2021/02/15
ISSN2399-3642
KeywordsAnimals, Antiparkinson Agents, Behavior, Animal, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Drug Repositioning, High-Throughput Screening Assays, Image Interpretation, Computer-Assisted, Machine Learning, Neural Networks, Computer, Posture, Proof of Concept Study, RNA Interference, Transaminases, Workflow
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.

DOI10.1038/s42003-021-01731-z
Alternate JournalCommun Biol
PubMed ID33589689
PubMed Central IDPMC7884385
Grant ListRF1 AG057341 / AG / NIA NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States
F32 AG062036 / AG / NIA NIH HHS / United States
R01 AG034446 / AG / NIA NIH HHS / United States
DP1 GM119167 / GM / NIGMS NIH HHS / United States