King, B. M. | bioRxiv Science

bioRxiv2025

Cognitive impairment and progressive neuroinflammation in mucopolysaccharidosis IIIA mice expressing the R245H Sgsh variant

Mucopolysaccharidosis (MPS) type IIIA (Sanfilippo syndrome) is an inherited childhood-onset dementia caused by insufficient SGSH enzymatic activity and subsequent accumulation of partially degraded heparan sulfate glycosaminoglycans. One of the most prevalent mutations is the Arg245His variant, representing up to 58% of mutations in some populations. Whilst other mouse models exist, none exhibit the mutations seen in humans, thus their amenability to testing of therapeutics such as pharmacological chaperones, which are often mutation-dependent, is limited. We have used CRISPR/Cas 9 gene editing to generate the first SgshR245H knock-in mouse model of MPS IIIA, which subsequently underwent extensive phenotyping. SgshR245H mouse brain exhibited progressive accumulation of heparan sulfate, endo/lysosomal system expansion and elevated levels of GFAP-reactive astroglial staining and activated microglia. Significant perturbation in several novel lipid species was observed in the CA1 region of the hippocampus using Matrix-Assisted Laser Desorption/Ionisation Mass Spectrometry Imaging. Spatial memory deficits were apparent in the Morris Water Maze probe and Y-maze tests, and Elevated Plus Maze exploration revealed reduced anxiety-like behaviours. SgshR245H MPS IIIA mice recapitulate key characteristics of the human disorder and represent a useful tool for studying disease pathogenesis and evaluating novel therapeutic approaches. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/691757v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@17ee5bforg.highwire.dtl.DTLVardef@1d7e23org.highwire.dtl.DTLVardef@445800org.highwire.dtl.DTLVardef@ed7dad_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Substrate reduction therapy in a Drosophila melanogaster model of Sanfilippo syndrome

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) types A, B, C or D, are neurodegenerative lysosomal storage disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism. Several treatments are under evaluation for these conditions including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, recent outcomes from a Phase III clinical trial have shown that high dose oral genistein does not significantly improve neurodevelopmental outcomes in MPS III patients. Here, we have tested an N-acetylglucosamine (GlcNAc) analogue inhibitor, 4-deoxy-GlcNAc peracetate, at reducing HS accumulation in cells from patients with Sanfilippo syndrome as a novel substrate reduction therapy. We then confirmed the capacity of this compound to modulate substrate accumulation in vivo in a Sanfilippo Drosophila model. Treatment with this compound significantly reduced HS in cultured MPS IIIA patient fibroblasts in a time-dependent manner. Neuronal and ubiquitous knockdown Drosophila models of MPS IIIC displaying elevated heparan sulfate and behavioural defects exhibited reduced HS burden relative to vehicle-treated controls following oral feeding with the GlcNAc analogue inhibitor. These findings indicate that this compound may be beneficial in slowing the accumulation of HS and may represent a novel therapeutic for Sanfilippo syndrome.

neuroscience↗