Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1β in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1β involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1β as a pivotal catalyst for neuropathological processes in MPS IIIA.

中文翻译：

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全身免疫挑战加剧了神经溶酶体疾病模型中的神经退行性变。


粘多糖贮积症 IIIA 型 （MPS IIIA） 是一种罕见的儿科溶酶体贮积症，由硫酸乙酰肝素进行性积累引起，导致神经认知能力下降和行为异常。儿科医生的个案报告表明，MPS IIIA 患者在感染后神经退行性变更严重，表明炎症是神经病理学的潜在驱动因素。为了检验这一假设，我们进行了急性研究，其中 WT 和 MPS IIIA 小鼠受到 TLR3 依赖性病毒模拟物 poly （I：C） 的攻击。急性高 poly （I：C） 剂量的攻击加剧了全身和脑细胞因子的表达，尤其是海马中的 IL-1β。这伴随着 MPS IIIA 小鼠大脑内 caspase-1 活性的增加，同时海马 GFAP 和 NeuN 表达的缺失。在低慢性 poly （I：C） 给药后，在 MPS IIIA 小鼠中也观察到相似水平的细胞损伤以及神经胶质增生的恶化。虽然需要进一步调查以充分了解 IL-1β 参与 MPS IIIA 加剧神经退行性的程度，但我们的数据有力地加强了我们之前的发现，表明 IL-1β 是 MPS IIIA 中神经病理过程的关键催化剂。