Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice
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Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice A. S. Azambuja 1,2 & L. N. Pimentel-Vera 2,3 & E. A. Gonzalez 2,3 & E. Poletto 2,3 & C. V. Pinheiro 2 & U. Matte 2,3 & R. Giugliani 2,3 & Guilherme Baldo 1,2,3 Received: 9 January 2020 / Accepted: 23 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Mucopolysaccharidosis type II . Hunter syndrome . Inflammasome . NRLP3 . Caspase-1 . Interleukin-1-beta . CRISPR-Cas9
Introduction Hunter syndrome or mucopolysaccharidosis type II (MPS II, OMIM 309900) is an X-linked recessive disease caused by the deficiency of the lysosomal hydrolase iduronate 2-sulfatase (IDS, EC3.1.6.13) resulting in accumulation of two glycosaminoglycans (GAG), heparan- and dermatan-sulfate (BrusiusFacchin et al. 2014). The disease is characterized by multisystemic abnormalities, including hepatosplenomegaly, joint contractures, dysostosis multiplex, cardiac and respiratory abnormalities. In the severe form, it also affects the central nervous system (CNS). Severe MPS II patients have
* Guilherme Baldo [email protected] 1
Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, UFRGS, Porto Alegre, Brazil
2
Centro de Terapia Gênica-HCPA, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil
3
Programa de Pós-Graduação em Genética e Biologia Molecular, UFRGS, Porto Alegre, Brazil
impairment of cognitive skills and regression of mental development (Giugliani et al. 2018). The mechanisms by which MPS II patients develop such brain abnormalities are not well-established. Storage of material in the lysosomes can be observed in neurons and glial cells. It has been shown in animal models that due to the storage, processes such as neuroinflammation, secondary accumulation of molecules as gangliosides and lysosome permeabilization occu
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