Abnormal intracellular trafficking of high affinity nerve growth factor receptor, Trk, in stable transfectants expressing presenilin 1 protein.
The pathogenesis of Alzheimer's disease (AD) is now thought to be tightly linked to Abeta deposition and oxidative stress, but it is still unknown how these factors result in neuronal dysfunction and cell death. Mutations of presenilin 1 (PS1) gene are the causative gene for early onset familial AD (FAD) due to the overproduction and deposition of pathogenic Abeta1-42 peptides. We report here the molecular influences of the overexpression of PS1 protein by stable transfection of PS1 cDNA into SH-SY5Y neuroblastoma cells on the function of high affinity nerve growth factor receptor, Trk, that is essential for neuronal survival and differentiation. We examined the sensitivity of these transfectants to oxidative stress and found that mutant (I143T) PS1-expressing clones showed the highest vulnerability to an oxidative stress inducer, hydrogen peroxide treatment compared with that of mock-transfected clones, whereas wild PS1-expressing cells were less vulnerable to the treatment than mutant PS1 transfectants. Because nerve growth factor (NGF) is known to protect neuronal cells from oxidative stress-induced cell death, we examined the NGF-Trk-mediated intracellular signaling pathway in these transfectants. In the wild and mutant PS1 cDNA-transfected cells, NGF did not elicit the autophosphorylation response of Trk, although their basal levels of tyrosine phosphorylation were higher than those of mock-transfected cells. Immunocytochemical and subcellular fractionation studies revealed that most of Trk proteins are abnormally located in the cytoplasm as well as in the nucleus in PS1-overexpressing clones irrespective of wild and mutant forms. These results strongly indicate that the expression level of PS1 protein has a cross talk with the Trk-dependent neuroprotective intracellular signaling pathway.
Hamano
Tadanori
T
The Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Mutoh
Tatsuro
T
Tabira
Takeshi
T
Araki
Wataru
W
Kuriyama
Masaru
M
Mihara
Takateru
T
Yano
Shigeaki
S
Yamamoto
Hiroko
H
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002451:Cell Compartmentation / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D053764:Presenilin-1; D021381:Protein Transport / Q000502:physiology; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection
D008565:Membrane Proteins; D016877:Oxidants; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020932:Nerve Growth Factor; D020917:Receptor, trkA