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
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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