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An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA
| Content Provider | MDPI |
|---|---|
| Author | Minna-Liisa, Änkö Douek, Alon Khabooshan, Mitra Amiri Henry, Jason Stamatis, Sebastian-Alexander Kreuder, Florian Ramm, Georg Wlodkowic, Donald Kaslin, Jan |
| Copyright Year | 2021 |
| Description | 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 $sgsh^{Δex5−6}$ zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. $sgsh^{Δex5−6}$ 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 $sgsh^{Δex5−6}$ zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in $sgsh^{Δex5−6}$ mutant larvae in a context-dependent manner. We expect the $sgsh^{Δex5−6}$ 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. |
| Starting Page | 5948 |
| e-ISSN | 14220067 |
| DOI | 10.3390/ijms22115948 |
| Journal | International Journal of Molecular Sciences |
| Issue Number | 11 |
| Volume Number | 22 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-05-31 |
| Access Restriction | Open |
| Subject Keyword | International Journal of Molecular Sciences Genetics Mucopolysaccharidosis Sanfilippo Syndrome Lysosomal Storage Disorder Childhood Dementia Heparan Sulfate Zebrafish Animal Disease Model Neuroinflammation Crispr/cas9 |
| Content Type | Text |
| Resource Type | Article |
