PUBLICATION
TARDBP (TDP-43) Knock-in Zebrafish Display a Late-Onset Motor Phenotype and Loss of Large Spinal Cord Motor Neurons
- Authors
- Harji, Z.A., Rampal, C.J., Rodríguez, E.C., Petel Légaré, V., Lissouba, A., Semmler, S., Liao, M., Ross, J.P., Rouleau, G.A., Vande Velde, C., Armstrong, G.A.B.
- ID
- ZDB-PUB-250828-6
- Date
- 2025
- Source
- Annals of neurology : (Journal)
- Registered Authors
- Armstrong, Gary A.B.
- Keywords
- none
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- Animals, Genetically Modified
- DNA-Binding Proteins*/genetics
- DNA-Binding Proteins*/metabolism
- Disease Models, Animal
- Gene Knock-In Techniques
- Motor Neurons*/metabolism
- Motor Neurons*/pathology
- Phenotype
- Spinal Cord*/metabolism
- Spinal Cord*/pathology
- Zebrafish
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 40862353 Full text @ Ann. Neurol.
Citation
Harji, Z.A., Rampal, C.J., Rodríguez, E.C., Petel Légaré, V., Lissouba, A., Semmler, S., Liao, M., Ross, J.P., Rouleau, G.A., Vande Velde, C., Armstrong, G.A.B. (2025) TARDBP (TDP-43) Knock-in Zebrafish Display a Late-Onset Motor Phenotype and Loss of Large Spinal Cord Motor Neurons. Annals of neurology. :.
Abstract
Objective Mutations in TARDBP (encoding TDP-43) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and include familial missense mutations where there are a lack of models and mechanisms examining how they are pathogenic.
Methods In this study, we developed 2 tardbp (Tdp-43) knock-in (KI) zebrafish mutant models encoding the analogous A382T and G348C variants and investigated their degenerative phenotypes.
Results We show that both models display reduced survival as well as an age-dependent motor phenotype that manifests at 1.5 years. Both variants in either the heterozygous or homozygous state did not impact protein expression levels of Tdp-43 in the central nervous system. However, homozygous G347C zebrafish displayed reduced expression levels of the tardbp transcript. We observed muscle cell atrophy starting at 1 year of age and loss of large spinal cord motor neurons in both KI models in older fish (2.35-3 years of age). We did not observe Tdp-43 aggregates. However, we did observe increased cytoplasmic Tdp-43 localization in spinal cord motor neurons in A379T zebrafish. At 1 year of age, whole spinal cord RNA-sequencing revealed an upregulation of neuroinflammatory transcripts in both models, as well as the selective downregulation of transcripts involved with synaptic function in G347C zebrafish, including syn2a, syn2b, syt2a, and stxbp1a.
Interpretation These novel models of common TDP-43 disease variants provide a unique opportunity to further our understanding of neurodegeneration in vivo and demonstrate that mutations in the same protein and domain can manifest with different phenotypes. ANN NEUROL 2025.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping