Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease

Marcelina Malinowska, Fiona L. Wilkinson, Kia J. Langford-Smith, Alex Langford-Smith, Jillian R. Brown, Brett E. Crawford, Marie T. Vanier, Grzegorz Grynkiewicz, Rob F. Wynn, J. Ed Wraith, Grzegorz Wegrzyn, Brian W. Bigger

    Research output: Contribution to journalArticlepeer-review

    98 Downloads (Pure)

    Abstract

    Background: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. Methodology/Principal Findings: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. Conclusions/Significance: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases. © 2010 Malinowska et al.
    Original languageEnglish
    Article numbere14192
    JournalPLoS ONE
    Volume5
    Issue number12
    DOIs
    Publication statusPublished - 2010

    Keywords

    • mucopolysaccharidosis
    • Sanfilippo
    • substrate reduction

    Fingerprint

    Dive into the research topics of 'Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease'. Together they form a unique fingerprint.

    Cite this