Low-molecular weight sulfated marine polysaccharides: Promising molecules to prevent neurodegeneration in mucopolysaccharidosis IIIA?

Abstract

Mucopolysaccharidosis IIIA is a hereditary disease caused by mutations in the sulfamidase enzyme that participates in catabolism of heparan sulfate (HS), leading to HS fragment accumulation and multisystemic failure. No cure exists and death occurs around the second decade of life. Two low molecular weight highly sulfated compounds derived from marine diabolican and infernan exopolysaccharides (A5_3 and A5_4, respectively) with heparanase inhibiting properties were tested in a MPSIIIA cell line model, resulting in limited degradation of intracellular HS. Next, we observed the effects of intraperitoneal injections of the diabolican derivative A5_3 from 4 to 12 weeks of age on MPSIIIA mice. Brain metabolism and microstructure, levels of proteins and genes involved in MPSIIIA brain pathophysiology were also investigated. 1H-Magnetic Resonance Spectroscopy (MRS) indicated deficits in energetic metabolism, tissue integrity and neurotransmission at both 4 and 12 weeks in MPSIIIA mice, with partial protective effects of A5_3. Ex-vivo Diffusion Tensor Imaging (DTI) showed white matter microstructural damage in MPSIIIA, with noticeable protective effects of A5_3. Protein and gene expression assessments displayed both pro-inflammatory and pro-apoptotic profiles in MPSIIIA mice, with benefits of A5_3 counteracting neuroinflammation. Overall, derivative A5_3 was well tolerated and was shown to be efficient in preventing brain metabolism failure and inflammation, resulting in preserved brain microstructure in the context of MPSIIIA.

• Authors: Noemi Veraldi, Isabelle Dentand Quadri, Yohan van de Looij, Laura Malaguti Modernell, Corinne Sinquin, Agata Zykwinska, Benjamin B Tournier, Fabien Dalonneau, Honglian Li, Jin-Ping Li, Philippe Millet, Romain Vives, Sylvia Colliec-Jouault, Ariane de Agostini, Eduardo Farias Sanches, Stéphane V Sizonenko
• Journal: Carbohydrate polymers (Carbohydr Polym) Vol. 320 Pg. 121214 (Nov 15 2023) ISSN: 1879-1344 [Electronic] England
• PMID: 37659814 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.