Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease).
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.
Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, United Kingdom.
Kim
K
Wager
Department of Neuroscience, Physiology and Pharmacology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, United Kingdom.|Department of Nephrology, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, United Kingdom.
Anselm A
AA
Zdebik
Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, United Kingdom.
Sonia
S
Fu
Pediatric Storage Disorders Laboratory, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 5 Cutcombe Road, London, SE5 9RX, United Kingdom.
Jonathan D
JD
Cooper
Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Robert J
RJ
Harvey
Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, United Kingdom.
Claire
http://orcid.org/0000-0002-6748-9301
C
Russell
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000002:abnormalities / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications* / Q000473:pathology; D055785:Gene Knockdown Techniques; D005911:Gliosis / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D060172:Morpholinos / Q000494:pharmacology / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009410:Nerve Degeneration / Q000150:complications* / Q000473:pathology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000150:complications* / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D016372:RNA, Antisense / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D015027:Zebrafish / Q000196:embryology / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D060172:Morpholinos; D021122:Protein Subunits; D016372:RNA, Antisense; D029961:Zebrafish Proteins; D025261:Mitochondrial Proton-Translocating ATPases