Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

Abstract

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.

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

“…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]. Storage bodies have been described in neurites in the cerebral cortex and the cerebellum [64], suggesting possible synaptic and neurotransmission defects.…”

“…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]. 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].…”

“…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.…”

“…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].…”

“…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]. It is possible, however, that incomplete gene targeting resulting in higher residual HGSNAT and GNS levels could explain the mild phenotype observed in the latter studies.…”