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bioRxiv · 10.64898/2025.12.02.691757

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

Lau, A. A.·Beard, H.·Trim, P. J.·King, B. M.·Snel, M. F.·Hemsley, K. M.
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Abstract

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

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Lau, A. A., Beard, H., Trim, P. J., King, B. M., Snel, M. F., Hemsley, K. M.. 2025-12-05. Cognitive impairment and progressive neuroinflammation in mucopolysaccharidosis IIIA mice expressing the R245H Sgsh variant. https://doi.org/10.64898/2025.12.02.691757

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