PMID- 24503862
OWN - NLM
STAT- MEDLINE
DCOM- 20141228
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 2
DP  - 2014
TI  - A monoclonal antibody TrkB receptor agonist as a potential therapeutic for 
      Huntington's disease.
PG  - e87923
LID - 10.1371/journal.pone.0087923 [doi]
LID - e87923
AB  - 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.
FAU - Todd, Daniel
AU  - Todd D
AD  - BioFocus, Saffron Walden, United Kingdom.
FAU - Gowers, Ian
AU  - Gowers I
AD  - BioFocus, Saffron Walden, United Kingdom.
FAU - Dowler, Simon J
AU  - Dowler SJ
AD  - BioFocus, Saffron Walden, United Kingdom.
FAU - Wall, Michael D
AU  - Wall MD
AD  - BioFocus, Saffron Walden, United Kingdom.
FAU - McAllister, George
AU  - McAllister G
AD  - BioFocus, Saffron Walden, United Kingdom.
FAU - Fischer, David F
AU  - Fischer DF
AD  - BioFocus, Leiden, Netherlands.
FAU - Dijkstra, Sipke
AU  - Dijkstra S
AD  - Galapagos, Leiden, Netherlands.
FAU - Fratantoni, Silvina A
AU  - Fratantoni SA
AD  - Galapagos, Leiden, Netherlands.
FAU - van de Bospoort, Rhea
AU  - van de Bospoort R
AD  - Galapagos, Leiden, Netherlands.
FAU - Veenman-Koepke, Jessica
AU  - Veenman-Koepke J
AD  - Galapagos, Leiden, Netherlands.
FAU - Flynn, Geraldine
AU  - Flynn G
AD  - Galapagos, Leiden, Netherlands.
FAU - Arjomand, Jamshid
AU  - Arjomand J
AD  - CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America 
      ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of 
      America.
FAU - Dominguez, Celia
AU  - Dominguez C
AD  - CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America 
      ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of 
      America.
FAU - Munoz-Sanjuan, Ignacio
AU  - Munoz-Sanjuan I
AD  - CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America 
      ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of 
      America.
FAU - Wityak, John
AU  - Wityak J
AD  - CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America 
      ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of 
      America.
FAU - Bard, Jonathan A
AU  - Bard JA
AD  - CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America 
      ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of 
      America.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140204
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neuroprotective Agents)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/chemistry/*pharmacology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line
MH  - Cells, Cultured
MH  - Corpus Striatum/cytology/drug effects
MH  - Disease Models, Animal
MH  - Drug Evaluation, Preclinical
MH  - Humans
MH  - Huntington Disease/drug therapy/*metabolism
MH  - Mice, Transgenic
MH  - Neurons/drug effects/metabolism
MH  - Neuroprotective Agents/chemistry/pharmacology
MH  - Rats
MH  - Receptor, trkB/*agonists/*metabolism
MH  - Signal Transduction/drug effects
PMC - PMC3913682
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/02/08 06:00
MHDA- 2014/12/30 06:00
PMCR- 2014/02/04
CRDT- 2014/02/08 06:00
PHST- 2013/11/18 00:00 [received]
PHST- 2013/12/20 00:00 [accepted]
PHST- 2014/02/08 06:00 [entrez]
PHST- 2014/02/08 06:00 [pubmed]
PHST- 2014/12/30 06:00 [medline]
PHST- 2014/02/04 00:00 [pmc-release]
AID - PONE-D-13-48531 [pii]
AID - 10.1371/journal.pone.0087923 [doi]
PST - epublish
SO  - PLoS One. 2014 Feb 4;9(2):e87923. doi: 10.1371/journal.pone.0087923. eCollection 
      2014.