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Evaluation of Disease Lesions in the Developing Canine MPS IIIA Brain
Leanne K Winner1, Neil R Marshall2, Robert D Jolly2
1Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Abstract:
Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited neurodegenerative disease of childhood that results in early death. Post-mortem studies have been carried out on human MPS IIIA brain, but little is known about early disease development. Here, we utilised the Huntaway dog model of MPS IIIA to evaluate disease lesion development from 2 to 24 weeks of age. A significant elevation in primarily stored heparan sulphate was observed in all brain regions assessed in MPS IIIA pups ≤9.5 weeks of age. There was a significant elevation in secondarily stored ganglioside (GM3 36:1) in ≤9.5-week-old MPS IIIA pup cerebellum, and other brain regions also exhibited accumulation of this lipid with time. The number of neural stem cells and neuronal precursor cells was essentially unchanged in MPS IIIA dog brain (c.f. unaffected) over the time course assessed, a finding corroborated by neuron cell counts. We observed early neuroinflammatory changes in young MPS IIIA pup brain, with significantly increased numbers of activated microglia recorded in all but one brain region in MPS IIIA pups ≤9.5 weeks of age (c.f. age-matched unaffected pups). In conclusion, infant-paediatric-stage MPS IIIA canine brain exhibits substantial and progressive primary and secondary substrate accumulation, coupled with early and robust microgliosis. Whilst early initiation of treatment is likely to be required to maintain optimal neurological function, the brain's neurodevelopmental potential appears largely unaffected by the disease process; further investigations confirming this are warranted.
Insights
Mucopolysaccharidosis IIIA (MPS IIIA) is a childhood neurodegenerative disease. Early MPS IIIA canine brain shows significant accumulation of heparan sulfate and gangliosides, with early microgliosis, but neurodevelopmental potential appears preserved.
Area of Science:
- Neuroscience
- Genetics
- Pediatric Diseases
Background:
- Mucopolysaccharidosis IIIA (MPS IIIA) is a severe inherited neurodegenerative disorder affecting children.
- Current understanding of early MPS IIIA brain development is limited, with most data from post-mortem human studies.
- The Huntaway dog model offers a valuable tool for studying the disease's early progression.
Purpose of the Study:
- To investigate early lesion development in the canine model of MPS IIIA from 2 to 24 weeks of age.
- To assess the accumulation of primary and secondary storage substrates in the developing MPS IIIA brain.
- To evaluate neuroinflammatory responses and neurodevelopmental markers in young MPS IIIA dogs.
Main Methods:
- Utilized the Huntaway dog model of MPS IIIA.
- Analyzed brain tissue from MPS IIIA pups aged 2 to 24 weeks.
- Quantified heparan sulfate and ganglioside accumulation.
- Assessed neural stem cell, neuronal precursor cell, and neuron counts.
- Measured the number of activated microglia.
Main Results:
- Significant elevation of heparan sulfate observed in all brain regions of MPS IIIA pups ≤9.5 weeks old.
- Accumulation of ganglioside GM3 (36:1) detected in the cerebellum and other brain regions over time.
- Neural stem cell and neuronal precursor cell numbers remained unchanged compared to unaffected controls.
- Early and significant increases in activated microglia (microgliosis) were found in most brain regions of young MPS IIIA pups.
Conclusions:
- Infant-stage MPS IIIA canine brains exhibit progressive primary and secondary substrate accumulation.
- Early and robust microgliosis is a hallmark of the disease in young MPS IIIA dogs.
- While early treatment is likely crucial, the brain's neurodevelopmental potential may remain largely unaffected in early stages.
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