PUBLICATION
Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer's disease risk genes
- Authors
- Kroll, F., Donnelly, J., Özcan, G.G., Mackay, E., Rihel, J.
- ID
- ZDB-PUB-250218-10
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Rihel, Jason
- Keywords
- Alzheimer's, Crispr, behaviour, neuroscience, pharmacology, sleep, small molecule screen, zebrafish
- MeSH Terms
-
- Zebrafish*/genetics
- Animals
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Behavior, Animal*/drug effects
- Disease Models, Animal
- Larva/drug effects
- Larva/genetics
- Alzheimer Disease*/drug therapy
- Alzheimer Disease*/genetics
- Signal Transduction*/drug effects
- Genetic Predisposition to Disease
- PubMed
- 39960847 Full text @ Elife
Citation
Kroll, F., Donnelly, J., Özcan, G.G., Mackay, E., Rihel, J. (2025) Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer's disease risk genes. eLIFE. 13:.
Abstract
By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer's risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer's risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3677 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping