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Title: Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: implication for neuroprotective therapies
Author: Brito, Verónica
Puigdellívol Cañadell, Maria del Mar
Giralt Torroella, Albert
Toro, Daniel del
Alberch i Vié, Jordi, 1959-
Ginés Padrós, Silvia
Keywords: Corea de Huntington
Genètica mèdica
Huntington's chorea
Medical genetics
Issue Date: 18-Apr-2013
Publisher: Nature Publishing Group
Abstract: Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed forHuntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models andHD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute todiminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75NTR) modulating TrkB signaling.Therefore, in this study we have analyzed the levels of p75NTRin several HD models, as well as in HD human brain. Our datademonstrates a p75NTR/TrkB imbalance in the striatum of two different HD mouse models,HdhQ111/111homozygous knockin miceand R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75NTRlevels in a HDcellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptoticcascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cellstransfected with p75NTRagainst 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 andBDNF. Altogether, our findings demonstrate that the p75NTR/TrkB imbalance induced by mutant huntingtin in striatal cellsassociated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerabilityin HD. On the basis of this data we hypothesize that normalization of p75NTRand/or TrkB expression or their signaling willimprove BDNF neuroprotective therapies in HD.
Note: Reproducció del document publicat a:
It is part of: Cell Death and Disease, 2013, vol. 4, num. 4, p. e595
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ISSN: 2041-4889
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Biomedicina)

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