PUBLICATION
A zebrafish model of acmsd deficiency does not support a prominent role for ACMSD in Parkinson's disease
- Authors
- Fargher, E., Keatinge, M., Pearce, O., Piepponen, P., Panula, P., van Eeden, F.J.M., MacDonald, R.B., Bandmann, O.
- ID
- ZDB-PUB-250510-2
- Date
- 2025
- Source
- NPJ Parkinson's disease 11: 118118 (Journal)
- Registered Authors
- Bandmann, Oliver, Keatinge, Marcus, MacDonald, Ryan, Panula, Pertti, van Eeden, Freek
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 40346140 Full text @ NPJ Parkinsons Dis
Citation
Fargher, E., Keatinge, M., Pearce, O., Piepponen, P., Panula, P., van Eeden, F.J.M., MacDonald, R.B., Bandmann, O. (2025) A zebrafish model of acmsd deficiency does not support a prominent role for ACMSD in Parkinson's disease. NPJ Parkinson's disease. 11:118118.
Abstract
Single nucleotide polymorphisms adjacent to the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) gene have been associated with Parkinson's disease (PD) in genome-wide association studies (GWAS). However, its biological validation as a PD risk gene has been hampered by the lack of available models. Using CRISPR/Cas9, we generated a zebrafish model of acmsd deficiency with marked increase in quinolinic acid. Despite this, acmsd-/- zebrafish were viable, fertile, morphologically normal and demonstrated no abnormalities in spontaneous movement. In contrast to the postulated pro-immune pathomechanism linking ACMSD to PD, microglial cells and expression of the proinflammatory cytokines cxcl8, il-1β, and mmp9 were similar between acmsd-/- and controls. The number of ascending dopaminergic neurons, and their susceptibility to MPP+, was also indistinguishable. An upregulation of kynurenine aminotransferase activity was identified in acmsd-/- zebrafish which may explain the absence of neurodegenerative phenotypes. Our study highlights the importance of biological validation for putative GWAS hits in suitable model systems.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping