PUBLICATION
ap4b1 -/- zebrafish demonstrate morphological and motor abnormalities
- Authors
- Rosengarten, H., D'Amore, A., Kim, H.M., Ebrahimi-Fakhari, D.
- ID
- ZDB-PUB-250424-5
- Date
- 2025
- Source
- Human molecular genetics : (Journal)
- Registered Authors
- Keywords
- adaptor protein complex 4, axon outgrowth, hereditary spastic paraplegia, zebrafish
- MeSH Terms
-
- Gene Editing
- Humans
- Seizures/genetics
- Animals
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Zebrafish*/genetics
- Spastic Paraplegia, Hereditary*/genetics
- Spastic Paraplegia, Hereditary*/pathology
- Spastic Paraplegia, Hereditary*/physiopathology
- CRISPR-Cas Systems
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Axons/metabolism
- Axons/pathology
- Disease Models, Animal
- PubMed
- 40267240 Full text @ Hum. Mol. Genet.
Citation
Rosengarten, H., D'Amore, A., Kim, H.M., Ebrahimi-Fakhari, D. (2025) ap4b1 -/- zebrafish demonstrate morphological and motor abnormalities. Human molecular genetics. :.
Abstract
Objective Hereditary spastic paraplegia type 47 (SPG47) is caused by biallelic loss-of-function variants in the AP4B1 gene, leading to neurodevelopmental and progressive motor impairment. This study aimed to generate and characterize a zebrafish (Danio rerio) model of SPG47 to investigate the role of ap4b1 in neurodevelopment and motor function.
Methods We employed CRISPR/Cas9 gene-editing to generate a stable ap4b1-/- zebrafish line. Behavioral, morphological, and motor function analyses were performed, including survival under stress conditions, spontaneous locomotor activity, light-dark transition assays, and coiling behavior. Axonal length was assessed via immunofluorescence targeting spinal motor neurons. Seizure susceptibility was evaluated using a PTZ paradigm.
Results ap4b1-/- zebrafish exhibited significantly reduced axonal length of spinal motor neurons, impaired motor function, and developmental malformations, including brachycephaly, reduced body length, bent spines, and craniofacial defects. Increased tail coiling and reduced spontaneous activity were observed in larvae, alongside absent habituation to light-dark stimuli. Under stress conditions, survival rates were significantly lower in the knockout group compared to controls. Despite early hyperexcitability, no significant increase in PTZ-induced seizures was observed.
Interpretation This study characterizes an ap4b1-/- zebrafish model that recapitulates some phenotypes of SPG47, including motor deficits and morphological abnormalities. These findings support the utility of zebrafish for studying AP-4 deficiency and provide a platform for investigating the molecular mechanisms underlying SPG47.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping