A novel conditional Sgsh knockout mouse model recapitulates phenotypic and neuropathic deficits of Sanfilippo syndrome

Abstract

Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (Sgsh ) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh mice prior to Sgsh mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, reactive astrocytosis and appearance of ubiquitin-positive inclusions) were also comparable between affected mouse strains. This suggests that gross substrate storage and these neuropathological markers are neither primary determinants, nor good biomarkers/indicators of symptom generation, confirming similar observations made recently in MPS-IIIA patients. The Sgsh mouse will be a useful tool for elucidation of the neurological basis of disease and assessment of the clinical efficacy of new treatments for Sanfilippo syndrome.

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

“…This storage pathology is found practically in all regions of the brain as well as in the spinal cord [63,65,68,73]. Concurrent storage of G M2 and G M3 gangliosides, primarily in neurons, is also found extensively throughout the brains of these mice [63][64][65][66][67]74,75]. Intriguingly, these gangliosides may co-localize with mitochondria, which are increased in number and by electron microscopy show morphological changes such as disorganized or lost cristae in the inner membrane [66,68].…”

“…Similar symptoms were detected when the mice were cross-bred to a congenic C57Bl/6 genetic background [64], as well as in a knockout MPS IIIB mouse [65], and a knockout model of MPS IIIC [66], though the age at which this became apparent varied. All mouse models showed storage of GAGs in the CNS as well as in peripheral organs such as the liver, kidney and spleen [63][64][65][66][67][68][69]. Motor deficits such as gait abnormalities, reduced grip strength or decreased performance in the rocking rotarod test were found in models of MPS IIIA [64,67,70] and MPS IIIB [71], mainly in older mice, recapitulating the human disease.…”

“…All mouse models showed storage of GAGs in the CNS as well as in peripheral organs such as the liver, kidney and spleen [63][64][65][66][67][68][69]. Motor deficits such as gait abnormalities, reduced grip strength or decreased performance in the rocking rotarod test were found in models of MPS IIIA [64,67,70] and MPS IIIB [71], mainly in older mice, recapitulating the human disease. Vision and hearing loss have also been recorded [71] and other sensory defects correlated with storage pathology in the peripheral nervous system [72].…”

“…Vision and hearing loss have also been recorded [71] and other sensory defects correlated with storage pathology in the peripheral nervous system [72]. Several mouse models developed hepatosplenomegaly as the disease progressed [63,67,68]. Most mouse models had a lifespan of approximately 7-12 months [63][64][65][66], but some lived longer; a mouse model of MPS IIID survived to a median age of 16 months [69] and a gene-targeted model of MPS IIIC survived to a median age of 21 months [68].…”

“…All MPS III mouse models show extensive CNS pathology. Accumulation of heparan sulfate, which is already present at birth [64,67], creates heterogeneous storage vacuoles within neurons and microglia that appear dense, laminated or clear by electron microscopy [63]. This storage pathology is found practically in all regions of the brain as well as in the spinal cord [63,65,68,73].…”