Hgsnat-flox Mouse

Hgsnat, or heparan-α-glucosaminide N-acetyltransferase, is an integral lysosomal membrane enzyme. It plays a crucial role in the degradation of heparan sulfate (HS) in the lysosome. Before HS can be degraded by glycosidases, Hgsnat acetylates the terminal glucosamine of HS, using the acetyl group from cytosolic acetyl-CoA in a unique transmembrane acetylation reaction [1,2,4,5,6]. Mutations in Hgsnat lead to HS accumulation, causing mucopolysaccharidosis IIIC, a lysosomal storage disease with progressive neurological deterioration and early death [1,5].

A novel HgsnatP304L mouse model, expressing misfolded HGSNAT Pro304Leu variant, presented earlier deficits in short-term and working/spatial memory compared to constitutive knockout Hgsnat-Geo mice. These mice also showed augmented neuroimmune response, synaptic deficits, and neuronal storage issues. Oral administration of glucosamine rescued memory deficits and most of the brain pathology, suggesting a potential chaperone therapy for patients with misfolded enzyme-causing mutations [3].

In conclusion, Hgsnat is essential for the proper degradation of HS in the lysosome. Mouse models like HgsnatP304L and Hgsnat-Geo have been valuable in revealing the role of Hgsnat in CNS-related pathologies, highlighting its importance in understanding and potentially treating mucopolysaccharidosis IIIC.