Hgsnat, short for heparan-α-glucosaminide N-acetyltransferase, is an integral lysosomal membrane enzyme. It plays a crucial role in the degradation of heparan sulfate (HS) in lysosomes. Before HS can be broken down by glycosidases, Hgsnat acetylates the terminal glucosamine of HS using the acetyl group from cytosolic acetyl-CoA in a unique transmembrane acetylation reaction [1,2,3,5,6]. This process is essential for the normal breakdown of HS into monosaccharides and free sulfate, and thus is important for maintaining normal cellular function [1,2,3,5,6].

In mouse models, the HgsnatP304L mouse, which expresses misfolded HGSNAT, shows earlier deficits in short-term and working/spatial memory compared to constitutive knockout Hgsnat-Geo mice. These mice also display an augmented severity of neuroimmune response, synaptic deficits, and neuronal storage of misfolded proteins and gangliosides. Oral administration of glucosamine, a HGSNAT chaperone, rescued memory deficits and most of the brain pathology in these mice, suggesting potential chaperone therapy for patients with HGSNAT-related disorders [4].

In conclusion, Hgsnat is essential for the lysosomal degradation of heparan sulfate. Studies using mouse models, such as the HgsnatP304L and Hgsnat-Geo mice, have revealed its role in maintaining normal neurological function. These models contribute significantly to understanding the pathophysiology of mucopolysaccharidosis IIIC, a lysosomal storage disease caused by Hgsnat deficiency, and provide insights into potential therapeutic strategies for this currently untreatable disorder [4].