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

Type Article
Date 2023-11
Language English
Author(s) Veraldi Noemi1, Quadri Isabelle Dentand2, Van De Looij Yohan3, 4, Modernell Laura Malaguti4, Sinquin CorinneORCID5, Zykwinska AgataORCID5, Tournier Benjamin B.6, Dalonneau Fabien7, Li Honglian8, Li Jin-Ping8, Millet Philippe6, Vives Romain7, Colliec Jouault SylviaORCID5, de Agostini Ariane1, 2, Farias Sanches Eduardo4, Sizonenko Stéphane V.4
Affiliation(s) 1 : Division of Clinical Pathology, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland
2 : Department of Pathology and Immunology, Faculty of Medicine, Geneva University, Geneva, Switzerland
3 : Center for Biomedical Imaging, Animal Imaging Technology section, Federal Polytechnic School of Lausanne, Lausanne, Switzerland
4 : Division of Development and Growth, Department of Pediatrics & Gynecology & Obstetrics, Children's Hospital, Geneva University Hospitals, Geneva, Switzerland
5 : Ifremer, Atlantic Center, MASAE, Nantes, France
6 : Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland
7 : University of Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France
8 : Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden
Source Carbohydrate Polymers (0144-8617) (Elsevier BV), 2023-11 , Vol. 320 , P. 121214 (15p.)
DOI 10.1016/j.carbpol.2023.121214
Keyword(s) Heparan sulfate, Mucopolysaccharidosis, Marine polysaccharides, Magnetic spectroscopy resonance
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.

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Veraldi Noemi, Quadri Isabelle Dentand, Van De Looij Yohan, Modernell Laura Malaguti, Sinquin Corinne, Zykwinska Agata, Tournier Benjamin B., Dalonneau Fabien, Li Honglian, Li Jin-Ping, Millet Philippe, Vives Romain, Colliec Jouault Sylvia, de Agostini Ariane, Farias Sanches Eduardo, Sizonenko Stéphane V. (2023). Low-molecular weight sulfated marine polysaccharides: Promising molecules to prevent neurodegeneration in mucopolysaccharidosis IIIA? Carbohydrate Polymers, 320, 121214 (15p.). Publisher's official version : https://doi.org/10.1016/j.carbpol.2023.121214 , Open Access version : https://archimer.ifremer.fr/doc/00847/95880/