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

Gustavo Monteiro Viana,Alexey V. Pshezhetsky,Esteban Alberto Gonzalez,Renan Pelluzzi Cavalheiro,Cinthia Castro do Nascimento,Vânia D’Almeida,Helena Bonciani Nader,Guilherme Baldo,Marcelo Andrade de Lima,Marcela Maciel Palacio Alvarez

doi:10.3390/ijms21041459

Abstract

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.

Highlights

Mucopolysaccharidoses (MPS) are inherited metabolic diseases, caused by a deficiency of lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs)
We demonstrate that lysosomal impairment in cortical neurons of MPS I mice is associated with overexpression of cathepsin B (CATB), its subsequent leakage from lysosomes to the cytoplasm, accumulation of amyloid aggregates, and massive neuroinflammation
To test our hypothesis that disruption of lysosomal homeostasis in brain cortex of MPS I (Idua -/-) mice leads to altered levels of lysosomal cathepsins and affects amyloidogenic amyloid precursor protein (APP) processing, we studied brain tissues for the signs of lysosomal storage, neuroinflammation, and accumulation of amyloid aggregates

Summary

Introduction

Mucopolysaccharidoses (MPS) are inherited metabolic diseases, caused by a deficiency of lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Mucopolysaccharidosis type I, or MPS I, is caused by the deficiency of the lysosomal enzyme α-l-iduronidase (IDUA; E.C. 3.2.1.76) involved in lysosomal catabolism of two specific GAGs: heparan sulfate (HS) and dermatan sulfate (DS). This causes HS and DS storage in cells of different tissues (e.g., brain, liver, kidney, heart, and bones) and increases their levels in urine and blood. Impairment of autophagy in the neurons has been related to the defective turnover and storage of other metabolites such as cholesterol and gangliosides (e.g., GM2 and GM3) This has been proposed to cause an intracellular metabolic imbalance and, loss of neuronal viability [16,17,18]

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