Systemic immune challenge exacerbates neurodegeneration in a model of neurological lysosomal disease

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. Synopsis A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C) and the impact on brain pathology was assessed. Exacerbated Il-1β levels and caspase-1 activity were observed in the serum and brain of MPS IIIA mice challenged with a high acute poly(I:C) dose. MPS IIIA spatial memory deficit worsened in a dose-dependent manner following chronic administration of poly(I:C). Existing microgliosis and astrogliosis were exacerbated in the cortex and amygdala of MPS IIIA mice following chronic poly(I:C) administration. Neuronal and astrocytic cell damage was observed in the hippocampus of MPS IIIA mice following chronic poly(I:C) administration. Il-1β and the inflammasome remain central to neuropathological progression in MPS IIIA, as confirmed by our previous findings. A more severe neurocognitive decline is documented in Mucopolysaccharidosis type IIIA (MPS IIIA) patients who contract viral infections. To explore the link between inflammation and neurodegeneration, MPS IIIA mice were challenged with the