Glucosamine Ameliorates Aggravated Neurological Phenotype in Mucopolysaccharidosis IIIC Mouse Expressing Misfolded HGSNAT Variant

Majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have allelic missense variants responsible for misfolding of heparan sulfate acetyl-CoA:alpha-glucosaminide Nacetyltransferase (HGSNAT) and potentially treatable with pharmacological chaperones. To test such strategy, we generated a novel model, the HgsnatP304L strain, expressing misfolded mutant HGSNAT with human missense mutation Pro304Leu. HgsnatP304L mice present deficits in short-term (novel object recognition test) and working/spatial (Y-maze test) memory at 4 months of age, 2-4 months earlier than previously described gene-targeted Hgsnat-Geo mice, which lack HGSNAT protein. HgsnatP304L mice also show augmented severity of synaptic deficits in CA1 neurons, and accelerated course of CNS pathology including neuronal storage of heparan sulfate, accumulation of misfolded proteins, increase in simple gangliosides and neuroimmune response as compared with Hgsnat-Geo mice. Our data for the first time demonstrate dominant-negative effects of the misfolded HGSNAT Pro304Leu variant and show that they are treatable by oral administration of glucosamine, suggesting that patients, affected with missense mutations preventing normal folding of the enzyme, could benefit from chaperone therapy.