Overexpression of BDNF and Full-Length TrkB Receptor Ameliorate Striatal Neural Survival in Huntington's Disease.

Abstract

BACKGROUND:

Several cellular mechanisms have been proposed to explain the pathogenesis of Huntington's disease (HD), including the lack of striatal brain-derived neurotrophic factor (BDNF). Thus, by preferentially binding to tropomyosin receptor kinase B (TrkB) receptor, BDNF is an important neurotrophin implicated in striatal neuronal survival.

OBJECTIVE:

To study the influence of BDNF and TrkB receptors in intracellular signaling pathways and caspase-3 activation in HD striatal cells.

METHODS:

HD mutant knockin and wild-type striatal cells were transduced with preproBDNF or full-length TrkB receptors to analyze BDNF processing, AKT and extracellular signal-regulated kinase (ERK) activation and the activity of caspase-3 in the absence or presence of staurosporine (STS).

RESULTS:

HD mutant cells transduced with preproBDNF-mCherry (mCh) expressed similar levels of pro- and mature BDNF compared to WT cells, but HD cells released lower levels of pro- and mature BDNF. Despite this, BDNF-mCh overexpression rescued decreased AKT phosphorylation and reduced the caspase-3 activation observed in HD cells. Activated ERK was also enhanced in HD BDNF-mCh/TrkB-eGFP receptor co-cultures. Of relevance, overexpression of TrkB-eGFP in HD cells decreased caspase-3 activation, and stimulation of TrkB-eGFP-transduced mutant cells with recombinant human BDNF reduced both basal and STS-induced caspase-3 activation.

CONCLUSION:

The results highlight the importance of BDNF-induced TrkB receptor signaling in rescuing HD-mediated apoptotic features in striatal cells.

• Authors: Ana Silva, Luana Naia, Alejandro Dominguez, Márcio Ribeiro, Joana Rodrigues, Otília V Vieira, Volkmar Lessmann, Ana Cristina Rego
• Journal: Neuro-degenerative diseases (Neurodegener Dis) Vol. 15 Issue 4 Pg. 207-18 ( 2015) ISSN: 1660-2862 [Electronic] Switzerland
• PMID: 25896770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Brain-Derived Neurotrophic Factor
• HTT protein, human
• Huntingtin Protein
• Membrane Glycoproteins
• Nerve Tissue Proteins
• Recombinant Proteins
• BDNF protein, human
• Protein-Tyrosine Kinases
• Receptor, trkB
• tropomyosin-related kinase-B, human
• Proto-Oncogene Proteins c-akt
• Caspase 3

Topics

• Apoptosis
• Brain-Derived Neurotrophic Factor (metabolism)
• Caspase 3 (metabolism)
• Cell Line
• Corpus Striatum (metabolism)
• Humans
• Huntingtin Protein
• Huntington Disease (metabolism)
• MAP Kinase Signaling System
• Membrane Glycoproteins (metabolism)
• Nerve Tissue Proteins (metabolism)
• Neurons (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, trkB
• Recombinant Proteins (metabolism)
• Signal Transduction