TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo.
Injury-induced downregulation of neurotrophin receptors may limit the response of neurons to trophic factors, compromising their ability to survive. We tested this hypothesis in a model of CNS injury: retinal ganglion cell (RGC) death after transection of the adult rat optic nerve. TrkB mRNA rapidly decreased in axotomized RGCs to approximately 50% of the level in intact retinas. TrkB gene transfer into RGCs combined with exogenous BDNF administration markedly increased neuronal survival: 76% of RGCs remained alive at 2 weeks after axotomy, a time when >90% of these neurons are lost without treatment. Activation of mitogen-activated protein kinase, but not phosphatidylinositol-3 kinase, was required for TrkB-induced survival. These data provide proof-of-principle that enhancing the capacity of injured neurons to respond to trophic factors can be an effective neuroprotective strategy in the adult CNS.
Cheng
Li
L
Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
Sapieha
Przemyslaw
P
Kittlerova
Pavla
P
Hauswirth
William W
WW
Di Polo
Adriana
A
D000818:Animals; D019771:Axotomy; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022761:Gene Transfer, Horizontal; D005822:Genetic Vectors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020813:Receptor, trkB; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases