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Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice


Malinowska, M and Wilkinson, FL and Bennett, WR and Langford-Smith, KJ and O'Leary, HA and Jakobkiewicz-Banecka, J and Wynn, R and Wraith, JE and Wegrzyn, G and Bigger, BW, Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice , Molecular Genetics and Metabolism: An International Journal, 98, (3) pp. 235-242. ISSN 1096-7192 (2009) [Refereed Article]

DOI: doi:10.1016/j.ymgme.2009.06.013


Mucopolysaccharidosis type IIIB (Sanfilippo syndrome) is a lysosomal storage disease caused by a genetic defect in the production of α-N-acetylglucosaminidase. This results in lysosomal and extracellular accumulation of the undegraded glycosaminoglycan (GAG) substrate, heparan sulphate. Affected patients show progressive CNS degeneration characterised by mental retardation, hyperactivity and seizures, with death usually in the mid teens to early twenties. Visceral organ storage is also present but is relatively mild compared to other MPS diseases storing similar substrates. No treatments currently exist for MPS IIIB. Genistein is a broad spectrum protein tyrosine kinase inhibitor which acts on several different growth factor receptors, notably EGF and IGF receptors, both of which are important for proteoglycan synthesis. Recent work has shown that genistein can reduce GAG synthesis in patients' fibroblasts in vitro and there is evidence in patients to suggest that it may be an effective substrate reduction therapy agent for MPS III. Here we have tested the dose responses of MPS IIIB mice to daily sub-chronic dosing of genistein in half log increments compared to carrier over 8 weeks. We show clear reductions in liver lysosome compartment size in both sexes and significant dose dependent improvements in total liver GAGs and hair morphology in male MPS IIIB animals following genistein treatment. Male MPS IIIB mice exhibited considerably more liver storage than females and responded better to treatment. No changes in total GAGs, lysosomal size or reactive astrogliosis in the brain cortex were observed after 8 weeks of treatment despite evidence that genistein can cross the blood brain barrier. This is the first demonstration of genistein treatment in MPS models in vivo. Crown Copyright © 2009.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Neurogenetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Bennett, WR (Dr Bill Bennett)
ID Code:63716
Year Published:2009
Web of Science® Times Cited:76
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-05-26
Last Modified:2011-07-28

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