Impaired TrkB-mediated ERK1/2 activation in huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression.
Altered neurotrophic support as a result of reduced brain-derived neurotrophic factor (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 phosphatidylinositol 3-kinase/Akt and phospholipase Cgamma 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 in neurotrophic deficits associated with HD pathology. Therefore, pharmacological approaches aimed to directly modulate the MAPK/ERK1/2 pathway may represent a valuable therapeutic strategy in HD.
Ginés
Silvia
S
Departament de Biologia Cel.lular, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain. silviagines@ub.edu
Paoletti
Paola
P
Alberch
Jordi
J
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003342:Corpus Striatum / Q000166:cytology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D020935:MAP Kinase Signaling System; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress; D010766:Phosphorylation; D020813:Receptor, trkB / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases