miércoles, 28 de julio de 2010

Impaired TrkB-mediated ERK1/2 activation in Huntington's disease knock-in striatal cells involves reduced p52/p46 Shc expression — JBC


Impaired TrkB-mediated ERK1/2 activation in Huntington's disease knock-in striatal cells involves reduced p52/p46 Shc expression
Silvia Gines*, Paola Paoletti and Jordi Alberch

+ Author Affiliations

Universitat de Barcelona. Institut d Investigacions Biomediques August Pi i Sunyer, Spain
* Corresponding author;
email: silviagines@ub.edu

Abstract
Altered neurotrophic support as a result of reduced BDNF expression and trafficking has been revealed as a key factor in Huntington disease (HD) pathology. BDNF binds to and activates the tyrosine kinase receptor TrkB leading to activation of intracellular signaling pathways to promote differentiation and cell survival. In order to design new neuroprotective therapies based on BDNF delivery it is important to define whether BDNF-mediated TrkB signaling is affected in HD. Here, we demonstrate reduced TrkB-mediated Ras/MAPK/ERK1/2 signaling but unchanged PI3K/Akt and PLC-γ activation in knock-in HD striatal cells. Altered BDNF-mediated ERK1/2 activation in mutant huntingtin cells is associated with reduced expression of p52/p46 Shc docking proteins. Notably, reduced BDNF-induced ERK1/2 activation increases the sensitivity of mutant huntingtin striatal cells to oxidative damage. Accordingly, pharmacological activation of the MAPK pathway with PMA prevents cell death induced by oxidative stress. Taken together our results suggest that in addition to reduced BDNF, diminished Ras/MAPK/ERK1/2 activation is involved on neurotrophic deficits associated to HD pathology. Therefore pharmacological approaches aimed to directly modulate the MAPK/ERK1/2 pathway may represent a valuable therapeutic strategy in HD.

abstract:
Impaired TrkB-mediated ERK1/2 activation in Huntington's disease knock-in striatal cells involves reduced p52/p46 Shc expression — JBC

full-text pdf, 25 pages:
http://www.jbc.org/content/early/2010/05/04/jbc.M109.084202.full.pdf+html

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