Neuropathology of murine Sanfilippo D syndrome

Mol Genet Metab. 2021 Dec;134(4):323-329. doi: 10.1016/j.ymgme.2021.11.010. Epub 2021 Nov 24.


Sanfilippo D syndrome (mucopolysaccharidosis type IIID) is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulfatase (GNS). A mouse model was generated by constitutive knockout of the Gns gene. We studied affected mice and controls at 12, 24, 36, and 48 weeks of age for neuropathological markers of disease in the somatosensory cortex, primary motor cortex, ventral posterior nuclei of the thalamus, striatum, hippocampus, and lateral and medial entorhinal cortex. We found significantly increased immunostaining for glial fibrillary associated protein (GFAP), CD68 (a marker of activated microglia), and lysosomal-associated membrane protein-1 (LAMP-1) in Sanfilippo D mice compared to controls at 12 weeks of age in all brain regions. Intergroup differences were marked for GFAP and CD68 staining, with levels in Sanfilippo D mice consistently above controls at all age groups. Intergroup differences in LAMP-1 staining were more pronounced in 12- and 24-week age groups compared to 36- and 48-week groups, as control animals showed some LAMP-1 staining at later timepoints in some brain regions. We also evaluated the somatosensory cortex, medial entorhinal cortex, reticular nucleus of the thalamus, medial amygdala, and hippocampal hilus for subunit c of mitochondrial ATP synthase (SCMAS). We found a progressive accumulation of SCMAS in most brain regions of Sanfilippo D mice compared to controls by 24 weeks of age. Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease pathogenesis and designing preclinical studies to test brain-directed treatments.

Keywords: Glycosaminoglycan; Lysosomal storage disease; Mucopolysaccharidosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / pathology*
  • Female
  • Gliosis / etiology
  • Lysosomal Membrane Proteins / analysis
  • Male
  • Mice
  • Microglia / physiology
  • Mitochondrial Proton-Translocating ATPases / analysis
  • Mucopolysaccharidosis III / etiology
  • Mucopolysaccharidosis III / metabolism
  • Mucopolysaccharidosis III / pathology*


  • Lamp1 protein, mouse
  • Lysosomal Membrane Proteins
  • mitochondrial ATPase subunit c
  • Mitochondrial Proton-Translocating ATPases