ZFIN ID: ZDB-PUB-160622-4
Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)
Wager, K., Zdebik, A.A., Fu, S., Cooper, J.D., Harvey, R.J., Russell, C.
Date: 2016
Source: PLoS One   11: e0157365 (Journal)
Registered Authors: Russell, Claire
Keywords: Zebrafish, Larvae, Lysosomes, Retina, Apoptosis, Chaperone proteins, Electroencephalography, Neuronal morphology
MeSH Terms:
  • Animals
  • Apoptosis/drug effects
  • Axons/drug effects
  • Axons/pathology
  • Behavior, Animal/drug effects
  • Brain/abnormalities
  • Brain/drug effects
  • Cell Proliferation/drug effects
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsy/complications*
  • Epilepsy/pathology
  • Gene Knockdown Techniques
  • Gliosis/pathology
  • Lysosomes/drug effects
  • Lysosomes/metabolism
  • Mitochondrial Proton-Translocating ATPases/metabolism
  • Morpholinos/pharmacology
  • Morpholinos/toxicity
  • Motor Activity/drug effects
  • Myocardium/pathology
  • Nerve Degeneration/complications*
  • Nerve Degeneration/pathology
  • Neuronal Ceroid-Lipofuscinoses/complications*
  • Neuronal Ceroid-Lipofuscinoses/pathology
  • Protein Subunits/metabolism
  • RNA, Antisense/metabolism
  • Retina/drug effects
  • Retina/pathology
  • Survival Analysis
  • Zebrafish/embryology
  • Zebrafish/physiology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 27327661 Full text @ PLoS One
The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80-85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery.