Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.
<h4>Background</h4>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 en...
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2010
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oai:doaj.org-article:bf2a9870d0f24a90bfb8ff75c88c78042021-11-18T07:02:12ZGenistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.1932-620310.1371/journal.pone.0014192https://doaj.org/article/bf2a9870d0f24a90bfb8ff75c88c78042010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21152017/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Marcelina MalinowskaFiona L WilkinsonKia J Langford-SmithAlex Langford-SmithJillian R BrownBrett E CrawfordMarie T VanierGrzegorz GrynkiewiczRob F WynnJ Ed WraithGrzegorz WegrzynBrian W BiggerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e14192 (2010) |
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Medicine R Science Q 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 Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Marcelina Malinowska |
| title |
Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| title_short |
Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| title_full |
Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| title_fullStr |
Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| title_full_unstemmed |
Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| title_sort |
genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/bf2a9870d0f24a90bfb8ff75c88c7804 |
| work_keys_str_mv |
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