Genetics and Molecular Pathology, SA Pathology (WCH site), Adelaide, Australia; Discipline of Paediatrics, The University of Adelaide, Adelaide, Australia.
Genetics and Molecular Pathology, SA Pathology (WCH site), Adelaide, Australia; Discipline of Genetics and Evolution, University of Adelaide, Australia.
Mol Genet Metab. 2020 Sep-Oct;131(1-2):197-205. doi: 10.1016/j.ymgme.2020.07.006. Epub 2020 Jul 25.
The cause of neurodegeneration in MPS mouse models is the focus of much debate and what the underlying cause of disease pathology in MPS mice is. The timing of development of pathology and when this can be reversed or impacted is the key to developing suitable therapies in MPS. This study is the first of its kind to correlate the biochemical changes with the functional outcome as assessed using non-invasive behaviour testing across multiple mucopolysaccharidosis (MPS) mouse models. In the MPS brain, the primary lysosomal enzyme dysfunction leads to accumulation of primary glycosaminoglycans (GAGs) with gangliosides (G and G) being the major secondary storage products. With a focus on the neuropathology, a time course experiment was conducted in MPS I, MPS IIIA, MPS VII (severe and attenuated models) in order to understand the relative timing and level of GAG and ganglioside accumulation and how this correlates to behaviour deficits. Time course analysis from 1 to 6 months of age was conducted on brain samples to assess primary GAG (uronic acid), β-hexosaminidase enzyme activity and levels of G and G gangliosides. This was compared to a battery of non-invasive behaviour tests including open field, inverted grid, rotarod and water cross maze were assessed to determine effects on motor function, activity and learning ability. The results show that the GAG and ganglioside accumulation begins prior to the onset of detectable changes in learning ability and behaviour. Interestingly, the highest levels of GAG and ganglioside accumulation was observed in the MPS IIIA mouse despite having 3% residual enzyme activity. Deficits in motor function were clearly observed in the severe Gus which were significantly delayed in the attenuated Gus model despite their minimal increase in detectable enzyme activity. This suggests that genotype and residual enzyme activity are not indicative of severity of disease pathology in MPS disease and there exists a window when there are considerable storage products without detectable functional deficits which may allow an alteration to occur with therapy.
神经退行性变在 MPS 小鼠模型中的病因是一个备受争议的问题，也是 MPS 小鼠疾病病理学的根本原因。病理学发展的时间以及何时可以逆转或影响病理学发展的时间，是在 MPS 中开发合适治疗方法的关键。这项研究首次将生化变化与使用多种黏多糖贮积症（MPS）小鼠模型进行的非侵入性行为测试评估的功能结果相关联。在 MPS 大脑中，主要溶酶体酶功能障碍导致主要糖胺聚糖（GAG）的积累，神经节苷脂（G 和 G）是主要的次要储存产物。本研究重点关注神经病理学，在 MPS I、MPS IIIA 和 MPS VII（严重和衰减模型）中进行了时间过程实验，以了解 GAG 和神经节苷脂积累的相对时间和水平，以及这与行为缺陷的相关性。对 1 至 6 月龄的脑样本进行了时间过程分析，以评估初级 GAG（尿嘧啶酸）、β-己糖胺酶活性和 G 和 G 神经节苷脂的水平。这与一系列非侵入性行为测试进行了比较，包括旷场、倒置网格、转棒和水交叉迷宫，以确定对运动功能、活动和学习能力的影响。结果表明，GAG 和神经节苷脂的积累始于学习能力和行为出现可检测变化之前。有趣的是，尽管 MPS IIIA 小鼠的残留酶活性为 3%，但其 GAG 和神经节苷脂的积累水平最高。严重 Gus 模型中明显观察到运动功能缺陷，尽管其可检测的酶活性增加最小，但衰减 Gus 模型中的缺陷明显延迟。这表明，基因型和残留酶活性不能说明 MPS 疾病病理学的严重程度，存在一个有大量储存产物而无可检测功能缺陷的窗口期，这可能允许治疗发生改变。
