An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA
Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme <i>N</i>-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS G...
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5948 |
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| author | Alon M. Douek Mitra Amiri Khabooshan Jason Henry Sebastian-Alexander Stamatis Florian Kreuder Georg Ramm Minna-Liisa Änkö Donald Wlodkowic Jan Kaslin |
| author_facet | Alon M. Douek Mitra Amiri Khabooshan Jason Henry Sebastian-Alexander Stamatis Florian Kreuder Georg Ramm Minna-Liisa Änkö Donald Wlodkowic Jan Kaslin |
| author_sort | Alon M. Douek |
| collection | DOAJ |
| description | Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme <i>N</i>-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 <i>sgsh<sup>Δex5−6</sup></i> zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. <i>sgsh<sup>Δex5−6</sup></i> 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 <i>sgsh<sup>Δex5−6</sup></i> zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in <i>sgsh<sup>Δex5−6</sup></i> mutant larvae in a context-dependent manner. We expect the <i>sgsh<sup>Δex5−6</sup></i> 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. |
| first_indexed | 2024-03-10T10:49:33Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:49:33Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2b8c5cdfa1064347a63ff21cb1db29932023-11-21T22:18:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211594810.3390/ijms22115948An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIAAlon M. Douek0Mitra Amiri Khabooshan1Jason Henry2Sebastian-Alexander Stamatis3Florian Kreuder4Georg Ramm5Minna-Liisa Änkö6Donald Wlodkowic7Jan Kaslin8Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, AustraliaAustralian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, AustraliaNeurotoxicology Lab, School of Science (Biosciences), RMIT University, Bundoora, VIC 3083, AustraliaAustralian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, AustraliaAustralian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, AustraliaRamaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC 3800, AustraliaCentre for Reproductive Health and Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, AustraliaNeurotoxicology Lab, School of Science (Biosciences), RMIT University, Bundoora, VIC 3083, AustraliaAustralian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, AustraliaMucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme <i>N</i>-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 <i>sgsh<sup>Δex5−6</sup></i> zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. <i>sgsh<sup>Δex5−6</sup></i> 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 <i>sgsh<sup>Δex5−6</sup></i> zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in <i>sgsh<sup>Δex5−6</sup></i> mutant larvae in a context-dependent manner. We expect the <i>sgsh<sup>Δex5−6</sup></i> 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.https://www.mdpi.com/1422-0067/22/11/5948mucopolysaccharidosisSanfilippo syndromelysosomal storage disorderchildhood dementiaheparan sulfatezebrafish |
| spellingShingle | Alon M. Douek Mitra Amiri Khabooshan Jason Henry Sebastian-Alexander Stamatis Florian Kreuder Georg Ramm Minna-Liisa Änkö Donald Wlodkowic Jan Kaslin An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA International Journal of Molecular Sciences mucopolysaccharidosis Sanfilippo syndrome lysosomal storage disorder childhood dementia heparan sulfate zebrafish |
| title | An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA |
| title_full | An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA |
| title_fullStr | An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA |
| title_full_unstemmed | An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA |
| title_short | An Engineered <i>sgsh</i> Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA |
| title_sort | engineered i sgsh i mutant zebrafish recapitulates molecular and behavioural pathobiology of sanfilippo syndrome a mps iiia |
| topic | mucopolysaccharidosis Sanfilippo syndrome lysosomal storage disorder childhood dementia heparan sulfate zebrafish |
| url | https://www.mdpi.com/1422-0067/22/11/5948 |
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