A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.
Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and...
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2014
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oai:doaj.org-article:d83601f6876548ceb4a63a9380b256702021-11-18T08:34:01ZA monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.1932-620310.1371/journal.pone.0087923https://doaj.org/article/d83601f6876548ceb4a63a9380b256702014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24503862/?tool=EBIhttps://doaj.org/toc/1932-6203Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.Daniel ToddIan GowersSimon J DowlerMichael D WallGeorge McAllisterDavid F FischerSipke DijkstraSilvina A FratantoniRhea van de BospoortJessica Veenman-KoepkeGeraldine FlynnJamshid ArjomandCelia DominguezIgnacio Munoz-SanjuanJohn WityakJonathan A BardPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e87923 (2014) |
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Medicine R Science Q Daniel Todd Ian Gowers Simon J Dowler Michael D Wall George McAllister David F Fischer Sipke Dijkstra Silvina A Fratantoni Rhea van de Bospoort Jessica Veenman-Koepke Geraldine Flynn Jamshid Arjomand Celia Dominguez Ignacio Munoz-Sanjuan John Wityak Jonathan A Bard A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| description |
Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models. |
| format |
article |
| author |
Daniel Todd Ian Gowers Simon J Dowler Michael D Wall George McAllister David F Fischer Sipke Dijkstra Silvina A Fratantoni Rhea van de Bospoort Jessica Veenman-Koepke Geraldine Flynn Jamshid Arjomand Celia Dominguez Ignacio Munoz-Sanjuan John Wityak Jonathan A Bard |
| author_facet |
Daniel Todd Ian Gowers Simon J Dowler Michael D Wall George McAllister David F Fischer Sipke Dijkstra Silvina A Fratantoni Rhea van de Bospoort Jessica Veenman-Koepke Geraldine Flynn Jamshid Arjomand Celia Dominguez Ignacio Munoz-Sanjuan John Wityak Jonathan A Bard |
| author_sort |
Daniel Todd |
| title |
A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| title_short |
A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| title_full |
A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| title_fullStr |
A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| title_full_unstemmed |
A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. |
| title_sort |
monoclonal antibody trkb receptor agonist as a potential therapeutic for huntington's disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/d83601f6876548ceb4a63a9380b25670 |
| work_keys_str_mv |
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1718421651201196032 |