Abstract
Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders.
Highlights
Mucopolysaccharidosis IIIA (MPS IIIA, OMIM #252900), or Sanfilippo Type A, is an autosomal recessive lysosomal storage disorder that affects 0.82 in 100,000 live births in the United Kingdom [1]
MPS IIIA is caused by mutations in the SGSH gene that result in deficiency of the N-sulfoglucosamine sulfohydrolase enzyme and subsequent accumulation of undegraded heparan sulphate, lysosomal enlargement and cellular and organ dysfunction [4,5,6,7]
We have attempted to perform a standardised analysis of MPS IIIA mice by first backcrossing them to the C57BL/6J background for over 10 generations and subsequently testing a cohort of MPS IIIA and wild type (WT) mice at the same circadian time point at 4, 6 and 8 months (16, 24 and 32 weeks) of age in the 60 minute open field test, the elevated plus maze, as well as several other neuromuscular evaluations that we have previously shown to be effective for phenotyping MPS IIIB mice [36]
Summary
Mucopolysaccharidosis IIIA (MPS IIIA, OMIM #252900), or Sanfilippo Type A, is an autosomal recessive lysosomal storage disorder that affects 0.82 in 100,000 live births in the United Kingdom [1]. There are no current therapies, several strategies are in development for MPS IIIA or the phenotypically indistinguishable MPS IIIB disease, including substrate reduction therapy [13,14,15], intrathecal enzyme replacement therapy [16,17,18,19,20] and gene therapy with lentiviral [21], adenoviral [22] or adeno-associated-viral [23] vectors. Biomarkers for MPS IIIA or related diseases are still in development [24,25], the accurate evaluation of neurodegeneration using behavioural phenotyping in the mouse model of disease is paramount. A spontaneously occurring mouse model of MPS IIIA on a mixed 129SvJ, C57BL/6, SJL, and CD1 background has been previously described with around 3% of normal enzyme activity and exhibiting many of the features observed in patients [26]. The MPS IIIA mouse model has been backcrossed to the C57BL/6 background by Professor John Hopwood’s Lysosomal Diseases Research Unit [30] and to the C57BL/6J background by Jackson laboratories [31]
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