Viana, GM, Gonzalez, EA, Palacio Alvarez, MM, Cavalheiro, RP, do Nascimento, CC, Baldo, G, D’Almeida, V, de Lima, MA, Pshezhetsky, A and Nader, HB (2020) Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex. International Journal of Molecular Sciences, 21 (4). ISSN 1422-0067

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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.

Item Type: Article
Additional Information: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: Alzheimer’s disease; amyloid precursor protein; cathepsin B; glycosaminoglycans; lysosomes; neuroinflammation.
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > R Medicine (General) > R735 Medical education. Medical schools. Research
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Symplectic
Date Deposited: 30 Apr 2020 08:09
Last Modified: 17 Aug 2020 14:45

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