Winner Leanne K, Marshall Neil R, Jolly Robert D, Trim Paul J, Duplock Stephen K, Snel Marten F, Hemsley Kim M
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand.
JIMD Rep. 2019;43:91-101. doi: 10.1007/8904_2018_110. Epub 2018 Jun 20.
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.
黏多糖贮积症IIIA型（MPS IIIA）是一种遗传性儿童神经退行性疾病，可导致早亡。已对人类MPS IIIA型大脑进行了尸检研究，但对疾病早期发展了解甚少。在此，我们利用MPS IIIA型的汉塔威犬模型评估2至24周龄时疾病病变的发展情况。在年龄≤9.5周的MPS IIIA幼犬评估的所有脑区中，均观察到主要储存的硫酸乙酰肝素显著升高。在年龄≤9.5周的MPS IIIA幼犬小脑中，次要储存的神经节苷脂（GM3 36:1）显著升高，其他脑区也随时间出现这种脂质的蓄积。在所评估的时间过程中，MPS IIIA犬脑（与未受影响的脑相比）中的神经干细胞和神经元前体细胞数量基本未变，这一发现得到神经元细胞计数的证实。我们在年幼的MPS IIIA幼犬脑中观察到早期神经炎症变化，在年龄≤9.5周的MPS IIIA幼犬（与年龄匹配的未受影响幼犬相比）中，除一个脑区外，所有脑区中活化小胶质细胞数量均显著增加。总之，婴幼儿期至儿童期的MPS IIIA犬脑表现出大量且进行性的原发性和继发性底物蓄积，以及早期且强烈的小胶质细胞增生。虽然可能需要尽早开始治疗以维持最佳神经功能，但大脑的神经发育潜力似乎在很大程度上不受疾病进程的影响；有必要进行进一步研究以证实这一点。
