PUBLICATION
Unveiling Immune System Perturbations in Early Development Through Zebrafish Models of NADHX Repair Deficiency
- Authors
- Patraskaki, M., Seyedkatouli, N., Schlicker, L., Warmoes, M.O., Cordero-Maldonado, M.L., Heins-Marroquin, U., Linster, C.L.
- ID
- ZDB-PUB-260203-6
- Date
- 2026
- Source
- Journal of inherited metabolic disease 49: e70149e70149 (Journal)
- Registered Authors
- Cordero-Maldonado, Maria Lorena, Heins-Marroquin, Ursula, Linster, Carole
- Keywords
- NAXD, NAXE, immune system, inborn errors of metabolism, metabolite repair, zebrafish
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems
- Disease Models, Animal
- Immune System*/metabolism
- Mutation
- NAD/metabolism
- Phenotype
- Racemases and Epimerases*/deficiency
- Racemases and Epimerases*/genetics
- Zebrafish
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 41621837 Full text @ J. Inherit. Metab. Dis.
Citation
Patraskaki, M., Seyedkatouli, N., Schlicker, L., Warmoes, M.O., Cordero-Maldonado, M.L., Heins-Marroquin, U., Linster, C.L. (2026) Unveiling Immune System Perturbations in Early Development Through Zebrafish Models of NADHX Repair Deficiency. Journal of inherited metabolic disease. 49:e70149e70149.
Abstract
The vital cofactors NADH and NADPH are prone to hydration, forming hydroxylated redox-inactive derivatives (NADHX and NADPHX) in cells. These damaged metabolites are repaired by two highly conserved enzymes, an NAD(P)HX dehydratase (NAXD) and an NAD(P)HX epimerase (NAXE). Mutations in NAXE or NAXD cause early onset progressive encephalopathy (PEBEL1 or PEBEL2), typically induced by fever or other triggers, and leading to premature death. To advance our comprehension of the disease mechanism and investigate potential therapeutic strategies, we generated zebrafish lines deficient in naxe or naxd using CRISPR/Cas9 technology. While both models accumulated NADHX, only naxd-/- larvae developed a severe phenotype, showing reduced locomotion and early death, which was partially rescued by nicotinic acid supplementation. Both mutant lines displayed signs of dysregulated immune function based on gene expression analyses and increased neutral red staining in the head region, indicating an increased number or activation of microglial cells. Our findings suggest that immune system perturbations play a role in PEBEL disease development, aligning with its inflammatory trigger-induced nature in humans. The naxd-/- model's responsiveness to nicotinic acid underscores its utility for preclinical drug screening. Overall, these models will be instrumental in furthering our understanding of PEBEL disease mechanisms and enhancing translational research efforts.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping