Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / pharmacology*
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Brain-Derived Neurotrophic Factor / metabolism
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Cell Death / drug effects
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Cell Line
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Cells, Cultured
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Corpus Striatum / cytology
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Corpus Striatum / drug effects
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Humans
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Huntington Disease / drug therapy
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Huntington Disease / metabolism*
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Mice, Transgenic
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Rats
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Receptor, trkB / agonists*
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Receptor, trkB / metabolism*
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Signal Transduction / drug effects
Substances
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Antibodies, Monoclonal
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Brain-Derived Neurotrophic Factor
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Neuroprotective Agents
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Receptor, trkB
Grants and funding
CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. The research described was conducted by BioFocus (UK and Netherlands) under a fee-for-service agreement from CHDI Foundation. The funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript.