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

ABSTRACT: 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.

SUBMITTER: Mandolfo O

PROVIDER: S-EPMC11251277 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Mandolfo Oriana O Parker Helen H Aguado Èlia È Ishikawa Learmonth Yuko Y Liao Ai Yin AY O'Leary Claire C Ellison Stuart S Forte Gabriella G Taylor Jessica J Wood Shaun S Searle Rachel R Holley Rebecca J RJ Boutin Hervé H Bigger Brian W BW

EMBO molecular medicine 20240618 7

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 challen ...[more]

PMID: 38890537

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

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

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