Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex
Autor: | Guilherme Baldo, Marcelo A. Lima, Alexey V. Pshezhetsky, Vânia D'Almeida, Gustavo Monteiro Viana, Renan P. Cavalheiro, Helena B. Nader, Esteban Alberto Gonzalez, Marcela Maciel Palacio Alvarez, Cinthia Castro do Nascimento |
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Rok vydání: | 2020 |
Předmět: |
Mucopolysaccharidosis I
cathepsin B amyloid precursor protein Q1 Cathepsin B neuroinflammation lcsh:Chemistry chemistry.chemical_compound Amyloid beta-Protein Precursor Mice 0302 clinical medicine Amyloid precursor protein skin and connective tissue diseases lcsh:QH301-705.5 Spectroscopy Cerebral Cortex Mice Knockout 0303 health sciences biology Glial fibrillary acidic protein Microglia Pyramidal Cells Neurodegeneration R735 General Medicine Computer Science Applications Cell biology medicine.anatomical_structure Alzheimer’s disease congenital hereditary and neonatal diseases and abnormalities Catalysis Dermatan sulfate Article Inorganic Chemistry 03 medical and health sciences Mucopolysaccharidosis type I lysosomes Glial Fibrillary Acidic Protein medicine Animals Physical and Theoretical Chemistry Molecular Biology Neuroinflammation 030304 developmental biology Organic Chemistry nutritional and metabolic diseases medicine.disease R1 chemistry lcsh:Biology (General) lcsh:QD1-999 glycosaminoglycans Astrocytes biology.protein 030217 neurology & neurosurgery |
Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 21, Iss 4, p 1459 (2020) Volume 21 Issue 4 |
ISSN: | 1422-0067 |
Popis: | Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of &alpha 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 &beta 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. |
Databáze: | OpenAIRE |
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