Abstract
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 (p75NTR) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75NTR in several HD models, as well as in HD human brain. Our data demonstrates a p75NTR/TrkB imbalance in the striatum of two different HD mouse models, HdhQ111/111 homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75NTR 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 p75NTR 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 p75NTR/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 p75NTR and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD.
Highlights
Expression has been reported in knockin Huntington’s disease (HD) cellular and mouse models, exon-1 HD transgenic mice and HD human brain,[2,3,4] which suggests that mutant huntingtin could lead to reduced neurotrophic support by altering brain-derived neurotrophic factor (BDNF) levels and by affecting TrkB expression
We found that BDNF prevented NMDA-mediated Akt phosphorylation in STHdh7/7Q cells (GFP or green fluorescent protein (GFP)-p75) suggesting that
We found an imbalance between p75NTR and TrkB expression in two distinct HD mouse models: HdhQ111/111 mutant knockin mice and R6/1 transgenic mice that was manifested in the putamen of HD patients supporting the idea that p75NTR/TrkB imbalance is relevant to HD pathology. p75NTR upregulation was associated with increased p75NTR mRNA expression, which agrees with previous studies showing increased p75NTR and reduced TrkB mRNA levels in the caudate of HD patients.[4]
Summary
P75NTR and TrkB protein levels are altered in the striatum of R6/1 mice. Reduced BDNF neuroprotection contributes to striatal vulnerability in HD.[17]. Given the importance of TrkB to mediate BDNF neuroprotection we analyzed whether the p75NTR/TrkB imbalance in HD might influence BDNF-induced cell survival To this aim adeno-associated viruses (AAV) expressing p75 shRNA or scramble shRNA were bilaterally injected into the striatum of wild-type and HD mice, corticostriatal slices obtained and cell survival analyzed following BDNF treatment (Figure 4). A significant increase (B20%) in p-JNK levels was found in extracts obtained from mutant corticostriatal slices treated with BDNF suggesting a correlation between levels of p-JNK and cell death (Figure 4c) Consistent with this idea reduction of p75NTR in wild-type and HD mice significantly decreased JNK phosphorylation (B25% and B15%, respectively, Figure 4c). To confirm a functional role for PP1 in the lack of BDNF neuroprotection GFP and GFPp75-transfected STHdh111/111Q cells were treated with OA to inhibit PP1 activity and p-Akt levels analyzed by western blot (Figure 8b). These results support the involvement of PP1 in the increased p75-mediated vulnerability of mutant huntingtin striatal cells to NMDA excitotoxicity
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