PMID- 23598407
OWN - NLM
STAT- MEDLINE
DCOM- 20131023
LR  - 20211021
IS  - 2041-4889 (Electronic)
VI  - 4
IP  - 4
DP  - 2013 Apr 18
TI  - Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: 
      implication for neuroprotective therapies.
PG  - e595
LID - 10.1038/cddis.2013.116 [doi]
AB  - Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) 
      administration have been proposed for Huntington's disease (HD) treatment. 
      However, our group has recently reported reduced levels of TrkB in HD mouse 
      models and HD human brain suggesting that besides a decrease on BDNF levels a 
      reduction of TrkB expression could also contribute to diminished neurotrophic 
      support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) 
      modulating TrkB signaling. Therefore, in this study we have analyzed the levels 
      of p75(NTR) in several HD models, as well as in HD human brain. Our data 
      demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse 
      models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also 
      manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) 
      levels in a HD cellular model did not affect BDNF-mediated TrkB activation of 
      prosurvival pathways but induced activation of apoptotic cascades as demonstrated 
      by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant 
      huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated 
      excitotoxicity, which was associated with decreased Akt phosphorylation. 
      Interestingly, lack of Akt activation following BDNF and NMDA treatment 
      correlated with increased PP1 levels. Accordingly, pharmacological inhibition of 
      PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced 
      by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB 
      imbalance induced by mutant huntingtin in striatal cells associated with the 
      aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to 
      increasing striatal vulnerability in HD. On the basis of this data we hypothesize 
      that normalization of p75(NTR) and/or TrkB expression or their signaling will 
      improve BDNF neuroprotective therapies in HD.
FAU - Brito, V
AU  - Brito V
AD  - Departament de Biologia Cel.lular, Immunologia i Neurociencies, Facultat de 
      Medicina, Universitat de Barcelona, Barcelona, Spain.
FAU - Puigdellivol, M
AU  - Puigdellivol M
FAU - Giralt, A
AU  - Giralt A
FAU - del Toro, D
AU  - del Toro D
FAU - Alberch, J
AU  - Alberch J
FAU - Gines, S
AU  - Gines S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130418
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Htt protein, mouse)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptor, Nerve Growth Factor)
RN  - 1W21G5Q4N2 (Okadaic Acid)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Brain-Derived Neurotrophic Factor/pharmacology/therapeutic use
MH  - Cell Line
MH  - Corpus Striatum/metabolism
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Knock-In Techniques
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/drug therapy/*metabolism/pathology
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Mice
MH  - N-Methylaspartate/pharmacology
MH  - Nerve Tissue Proteins/genetics/metabolism
MH  - Nuclear Proteins/genetics/metabolism
MH  - Okadaic Acid/pharmacology
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Phosphatase 1/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Putamen/metabolism
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Receptor, Nerve Growth Factor/antagonists & inhibitors/genetics/*metabolism
MH  - Receptor, trkB/*metabolism
MH  - Signal Transduction
PMC - PMC3641339
EDAT- 2013/04/20 06:00
MHDA- 2013/10/24 06:00
PMCR- 2013/04/01
CRDT- 2013/04/20 06:00
PHST- 2013/04/20 06:00 [entrez]
PHST- 2013/04/20 06:00 [pubmed]
PHST- 2013/10/24 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - cddis2013116 [pii]
AID - 10.1038/cddis.2013.116 [doi]
PST - epublish
SO  - Cell Death Dis. 2013 Apr 18;4(4):e595. doi: 10.1038/cddis.2013.116.