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Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice
A S Azambuja1,2, L N Pimentel-Vera2,3, E A Gonzalez2,3
1Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, UFRGS, Porto Alegre, Brazil.
Abstract:
Hunter syndrome or mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by the deficiency of iduronate 2-sulfatase (IDS), leading to storage of undegraded heparan and dermatan sulfate. Patients with the severe form present neurological abnormalities, but the mechanisms of such alterations are unknown. Here, we hypothesized that the undegraded substances found in this disease could be recognized as damage-associated molecular patterns (DAMPS), leading to activation of the inflammasome. Brains from 2 and 5 months normal and MPS II mice were studied. We observed an increase in cathepsin B activity in the brain tissue and leakage of this enzyme from the lysosome to the cytoplasm in a MPS II neuronal cell line, which is a known activator of the inflammasome. Furthermore, Caspase-1 activity and IL-1-beta levels were elevated at 5 months, confirming that this pathway is indeed altered. Our results suggest that undegraded GAG activate the inflammasome pathway in MPS II and future studies could focus on blocking such pathway to better understand the role of this process to the pathogenesis of MPS II.
Insights
Hunter syndrome (MPS II) involves neurological issues due to undegraded substances activating the inflammasome pathway. This research suggests blocking this pathway may offer therapeutic benefits for MPS II.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Hunter syndrome (mucopolysaccharidosis type II) is an X-linked recessive disorder caused by iduronate 2-sulfatase (IDS) deficiency.
- This deficiency leads to the accumulation of undegraded heparan and dermatan sulfate, particularly affecting neurological function in severe cases.
- The precise mechanisms underlying neurological abnormalities in MPS II remain largely unknown.
Purpose of the Study:
- To investigate the hypothesis that undegraded substances in MPS II act as damage-associated molecular patterns (DAMPs).
- To explore the potential activation of the inflammasome pathway by these DAMPs in the context of MPS II neurological pathology.
- To identify potential therapeutic targets by elucidating the role of inflammasome activation in MPS II pathogenesis.
Main Methods:
- Comparative analysis of brain tissue from normal and MPS II mice at 2 and 5 months of age.
- Assessment of cathepsin B activity and its subcellular localization in MPS II neuronal cell lines.
- Measurement of Caspase-1 activity and Interleukin-1 beta (IL-1β) levels in affected brain tissue.
Main Results:
- Increased cathepsin B activity was observed in the brain tissue of MPS II mice.
- Evidence of cathepsin B leakage from lysosomes to the cytoplasm was found in MPS II neuronal cells, indicating inflammasome activation.
- Elevated Caspase-1 activity and IL-1β levels at 5 months in MPS II mice confirm inflammasome pathway alteration.
Conclusions:
- Undegraded glycosaminoglycans (GAGs) in MPS II appear to activate the inflammasome pathway.
- This activation contributes to the neurological abnormalities observed in Hunter syndrome.
- Targeting the inflammasome pathway presents a potential therapeutic strategy for MPS II.
