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

Author(s)

Viana, Gustavo Monteiro ^[1] ; Gonzalez, Esteban Alberto ^[2] ; Palacio Alvarez, Marcela Maciel ^[1] ; Cavalheiro, Renan Pelluzzi ^[1] ; do Nascimento, Cinthia Castro ^[3] ; Baldo, Guilherme ^[2] ; D'Almeida, Vania ^[3] ; de Lima, Marcelo Andrade ^[4] ; Pshezhetsky, V, Alexey ; Nader, Helena Bonciani ^[1]

Affiliation

^[1] Univ Fed Sao Paulo UNIFESP, Dept Biochem, BR-04044020 Sao Paulo, SP - Brazil

^[2] Hosp Clin Porto Alegre, Gene Therapy Ctr, BR-90035903 Porto Alegre, RS - Brazil

^[3] Univ Fed Sao Paulo UNIFESP, Dept Psychobiol, BR-04024002 Sao Paulo, SP - Brazil

^[4] Keele Univ, Sch Life Sci, Mol & Struct Biosci, Huxley Bldg, Keele ST5 5BG, Staffs - England

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 4 FEB 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 17/14179-3 - Vesicle trafficking during heparan sulfate biosynthesis
• Grantee: Ivarne Luis dos Santos Tersariol
• Support type: Regular Research Grants
• FAPESP's process: 18/17003-6 - Glycosaminoglycans as triggers of neurodegeneration in MPS IIIC and Alzheimer's Disease
• Grantee: Gustavo Monteiro Viana
• Support type: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 15/03964-6 - Glycosaminoglycans and proteoglycans: interplay between structure and function
• Grantee: Helena Bonciani Nader
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 16/25486-1 - Glycosaminoglycans and activation of amyloidogenic pathway in mucopolysaccharidosis type I
• Grantee: Gustavo Monteiro Viana
• Support type: Scholarships in Brazil - Post-Doctorate