Pericleous Kleopatra, McIntyre Chantelle, Fuller Maria
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide 5006, Australia.
School of Biological Sciences, University of Adelaide, Adelaide 5000, Australia.
Mol Genet Metab Rep. 2023 Jun 10;36:100985. doi: 10.1016/j.ymgmr.2023.100985. eCollection 2023 Sep.
Mucopolysaccharidosis type IIIA (MPS IIIA) is an inherited metabolic disorder caused by a lysosomal enzyme deficiency resulting in heparan sulphate (HS) accumulation and manifests with a progressive neurodegenerative phenotype. A naturally occurring MPS IIIA mouse model is invaluable for preclinical evaluation of potential treatments but the ability to effectively assess neurological function has proved challenging. Here, the aim was to evaluate a set of behaviour tests for their reliability in assessing disease progression in the MPS IIIA mouse model. Compared to wild-type (WT) mice, MPS IIIA mice displayed memory and learning deficits in the water crossmaze from mid-stage disease and locomotor impairment in the hind-limb gait assessment at late-stage disease, supporting previous findings. Declined wellbeing was also observed in the MPS IIIA mice via burrowing and nest building evaluation at late-stage disease compared to WT mice, mirroring the progressive nature of neurological disease. Excessive HS accumulation observed in the MPS IIIA mouse brain from 1 month of age did not appear to manifest as abnormal behaviours until at least 6 months of age suggesting there may be a threshold of HS accumulation before measurable neurocognitive decline. Results obtained from the open field and three-chamber sociability test are inconsistent with previous studies and do not reflect MPS IIIA patient disease progression, suggesting these assessments are not reliable. In conclusion, water cross-maze, hind-limb gait, nest building and burrowing, are promising assessments in the MPS IIIA mouse model, which produce consistent results that mimic the human disease.
ⅢA型黏多糖贮积症（MPS IIIA）是一种遗传性代谢紊乱疾病，由溶酶体酶缺乏引起，导致硫酸乙酰肝素（HS）蓄积，并表现出进行性神经退行性表型。一种自然发生的MPS IIIA小鼠模型对于潜在治疗方法的临床前评估具有重要价值，但有效评估神经功能的能力已被证明具有挑战性。在此，目的是评估一组行为测试在评估MPS IIIA小鼠模型疾病进展方面的可靠性。与野生型（WT）小鼠相比，MPS IIIA小鼠在疾病中期的水迷宫试验中表现出记忆和学习缺陷，在疾病后期的后肢步态评估中表现出运动障碍，这支持了先前的研究结果。与WT小鼠相比，在疾病后期通过打洞和筑巢评估还观察到MPS IIIA小鼠的健康状况下降，这反映了神经疾病的进行性本质。在MPS IIIA小鼠大脑中从1月龄开始观察到的过量HS蓄积，直到至少6月龄时才表现为异常行为，这表明在可测量的神经认知衰退之前可能存在HS蓄积阈值。从旷场试验和三室社交性试验获得的结果与先前的研究不一致，且不能反映MPS IIIA患者的疾病进展，这表明这些评估不可靠。总之，水迷宫试验、后肢步态、筑巢和打洞试验在MPS IIIA小鼠模型中是有前景的评估方法，它们产生的一致结果模拟了人类疾病。
