An engineered sgsh Mutant Zebrafish recapitulates molecular and behavioural pathobiology of sanfilippo syndrome A/MPS IIIA

Abstract

<p>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 highthroughput screening. The sgsh<sup>Δex5−6</sup> zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgsh<sup>Δex5−6</sup> 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<sup>Δex5−6</sup> 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<sup>Δex5−6</sup> mutant larvae in a context‐dependent manner. We expect the sgsh<sup>Δex5−6</sup> 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.</p>