A zebrafish model of acmsd deficiency does not support a prominent role for ACMSD in Parkinson’s disease
Year: 2025
Type: article
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.
Source: npj Parkinson s Disease
Authors: Emma Fargher, Marcus Keatinge, Oluwaseyi Pearce, Petteri Piepponen, Pertti Panula, Fredericus J. M. van Eeden, Ryan B. MacDonald, Oliver Bandmann
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
Awards: In vivo pathway analysis to determine the mechanistic role of susceptibility genes for Parkinson's disease, Developing an in vivo CRISPR-interference Screening Resource, Glucocerebrosidase mutations in Parkinson disease:molecular pathogenesis,and the basis for personalised therapy with small molecule chaperones
OpenAlex ID: W4410216716