Glycosaminoglycans and activation of amyloidogenic pathway in mucopolysaccharidosis type I

Abstract

Mucopolysaccharidosis type I (MPS I) is an autossomic recessive disease caused by lysosomal alfa-L-iduronidase deficiency, leading to accumulation of glycosaminoglycans (GAGs), mainly heparin and dermatan sulfate, in several organs and tissues. In addition to deposit, structural modifications in accumulated GAG chains can also affect the signalization of different molecules including growth factors, cytokines and even other lysosomal enzymes. Some studies indicated that, in the central nervous system, Cathepsins B and D can also participate in amyloid precursor protein (APP) proteolytic processing, which could lead to abnormal production of ²-amyloid peptides and, consequently, to deposition of amyloid senile plaques. Thus, the present project aims to investigate a possible activation of pro-amyloidogenic pathway in brain tissues from MPS I mice as well as in normal (SH-SY5Y) and IDUA-silenced (SH-IDUA) human neuroblastoma derived cells. For this purpose, structural and quantitative analysis of accumulated GAG, as well its potential interactions with both Cathepsins B and D and possible alterations in APP processing. Different methodologies will be performed such as confocal and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, high performance liquid chromatography (HPLC), mass spectrometry, biochemical (enzymatic activity and Western blotting) and molecular assays (genome editing). Structural characterization of accumulated GAGs and its interplay in protein network in MPS I tissues and cells allows a better understanding about potential mechanisms related to the amyloidogenic APP processing, bringing evidences of a possible role of lysosomal dysregulation as a pathological mechanism also related to Alzheimer's Disease. (AU)