skip to Main Content
Cellular and molecular mechanisms underlying the neuronal dysfunction in Hunter syndrome

Project description

Hunter syndrome, or mucopolysaccharidosis type II, is a progressive and multisystem disease caused by mutations in a gene coding for a lysosomal enzyme called iduronate-2-sulfatase. This enzyme enables the degradation and thus regulates the levels of several glycosaminoglycans, such as heparan sulfate proteoglycans or dermatan sulfate proteoglycans, which are key components of the extracellular matrix. As a consequence, people carrying mutations in this lysosomal enzyme accumulate very high levels of glycosaminoglycans, particularly heparan sulfate proteoglycans in the nervous system, which severely impacts neuronal function. Other glycosaminoglycans and components of the extracellular matrix also accumulate. It appears that cells in the central nervous system are especially susceptible to heparan sulfate proteoglycans levels, but the roles of heparan sulfate proteoglycans in this disease are not fully understood. In addition, lysosomal dysfunction also profoundly affects glial cells, which are the most abundant cell type in the brain, leading to their degeneration, and eventually to neurodegeneration. Yet, this not well understood in the context of mucopolysaccharidoses. This research project aims to elucidate how dysregulated heparan sulfate proteoglycans impacts lysosomal function and other aspects of the cell biology of neurons and glia, as well as the extracellular matrix that surrounds them. We use the model organism C. elegans to effectively address these questions in vivo. We will analyse an array of genetic mutations and molecular overexpression conditions, following the evolution of neurons and glia with single-cell resolution, assessing the dynamics of their lysosomes, autophagosomes and other intracellular organelles, as well as of the extracellular matrix where heparan sulfate proteoglycans reside, with fluorescent reporters in live animals. This work is expected to contribute to the identification if new therapeutic avenues that may lead to improved strategies of prevention and treatment for patients affected by the Hunter syndrome.

Research team

Name: Ivan VALETTE, BSc and Marin PASCAL, BSc
Supervisor: Claire Bénard (UQAM)
Laureate: Co-recipients of the 2022 Félix-Antoine Aublet Scholarship

Back To Top