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

AimsMucopolysaccharidosis (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, their applicability to, and translational delivery of, clinically relevant pharmacological chaperones is limited. We therefore aimed to generate and characterise a novel SgshR245H knock-in mouse model of MPS IIIA. MethodsCRISPR/Cas 9 gene editing introduced the SgshR245H mutation, and a breeding colony was established. Mouse behaviour was evaluated in a test battery; SGSH activity and heparan sulfate levels were measured using fluorometric and mass spectrometric assays, respectively; and histological staining was undertaken to characterise brain pathology. ResultsSpatial memory and learning deficits were apparent in the Morris Water Maze probe and Y-maze tests. Elevated Plus Maze exploration revealed reduced anxiety-like behaviours. SgshR245H mice exhibited progressive accumulation of brain heparan sulfate and elevated levels of GFAP-reactive astroglial staining and activated microglia. ConclusionSgshR245H MPS IIIA mice recapitulate key characteristics of the human disorder, representing a useful tool for studying disease pathogenesis and evaluating novel therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/691757v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@192e9dorg.highwire.dtl.DTLVardef@1436023org.highwire.dtl.DTLVardef@5ccbb8org.highwire.dtl.DTLVardef@42a465_HPS_FORMAT_FIGEXP M_FIG C_FIG