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Open AccessArticle

Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

1
Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04044-020, Brazil
2
Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
3
Department of Psychobiology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04024-002, Brazil
4
Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK
5
Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, Canada
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1459; https://doi.org/10.3390/ijms21041459
Received: 22 January 2020 / Revised: 12 February 2020 / Accepted: 12 February 2020 / Published: 20 February 2020
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)
Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration. View Full-Text
Keywords: glycosaminoglycans; cathepsin B; Alzheimer’s disease; amyloid precursor protein; lysosomes; neuroinflammation glycosaminoglycans; cathepsin B; Alzheimer’s disease; amyloid precursor protein; lysosomes; neuroinflammation
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MDPI and ACS Style

Viana, G.M.; Gonzalez, E.A.; Alvarez, M.M.P.; Cavalheiro, R.P.; do Nascimento, C.C.; Baldo, G.; D’Almeida, V.; de Lima, M.A.; Pshezhetsky, A.V.; Nader, H.B. Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex. Int. J. Mol. Sci. 2020, 21, 1459. https://doi.org/10.3390/ijms21041459

AMA Style

Viana GM, Gonzalez EA, Alvarez MMP, Cavalheiro RP, do Nascimento CC, Baldo G, D’Almeida V, de Lima MA, Pshezhetsky AV, Nader HB. Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex. International Journal of Molecular Sciences. 2020; 21(4):1459. https://doi.org/10.3390/ijms21041459

Chicago/Turabian Style

Viana, Gustavo M.; Gonzalez, Esteban A.; Alvarez, Marcela M.P.; Cavalheiro, Renan P.; do Nascimento, Cinthia C.; Baldo, Guilherme; D’Almeida, Vânia; de Lima, Marcelo A.; Pshezhetsky, Alexey V.; Nader, Helena B. 2020. "Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex" Int. J. Mol. Sci. 21, no. 4: 1459. https://doi.org/10.3390/ijms21041459

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