title: Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Mucopolysaccharidosis Stem Cell Research Group, Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Marcelina
authors.initials: M
authors.lastname: Malinowska
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Wilkinson
authors.forename: Kia J
authors.initials: KJ
authors.lastname: Langford-Smith
authors.forename: Alex
authors.initials: A
authors.lastname: Langford-Smith
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Brown
authors.forename: Brett E
authors.initials: BE
authors.lastname: Crawford
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grynkiewicz
authors.forename: Rob F
authors.initials: RF
authors.lastname: Wynn
authors.forename: J Ed
authors.initials: JE
authors.lastname: Wraith
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wegrzyn
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000737:chemistry; D006579:Heterozygote; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009084:Mucopolysaccharidosis III / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D019833:Genistein; D006497:Heparan Sulfate; D047428:Protein Kinase Inhibitors