PUBLICATION
An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA
- Authors
- Douek, A.M., Amiri Khabooshan, M., Henry, J., Stamatis, S.A., Kreuder, F., Ramm, G., Änkö, M.L., Wlodkowic, D., Kaslin, J.
- ID
- ZDB-PUB-210603-38
- Date
- 2021
- Source
- International Journal of Molecular Sciences 22(11): (Journal)
- Registered Authors
- Douek, Alon M., Kaslin, Jan
- Keywords
- CRISPR/Cas9, Sanfilippo syndrome, animal disease model, childhood dementia, heparan sulfate, lysosomal storage disorder, mucopolysaccharidosis, neuroinflammation, zebrafish
- MeSH Terms
-
- Animals
- Disease Models, Animal*
- Humans
- Hydrolases/genetics*
- Mucopolysaccharidosis III*/metabolism
- Mucopolysaccharidosis III*/pathology
- Mutation
- Phenotype
- Zebrafish
- PubMed
- 34073041 Full text @ Int. J. Mol. Sci.
Citation
Douek, A.M., Amiri Khabooshan, M., Henry, J., Stamatis, S.A., Kreuder, F., Ramm, G., Änkö, M.L., Wlodkowic, D., Kaslin, J. (2021) An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA. International Journal of Molecular Sciences. 22(11):.
Abstract
Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgshΔex5-6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgshΔex5-6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgshΔex5-6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgshΔex5-6 mutant larvae in a context-dependent manner. We expect the sgshΔex5-6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping