Abnormal intracellular trafficking of high affinity nerve growth factor receptor, Trk, in stable transfectants expressing presenilin 1 protein

Tadanori Hamano, Tatsuro Mutoh, Takeshi Tabira, Wataru Araki, Masaru Kuriyama, Takateru Mihara, Shigeaki Yano, Hiroko Yamamoto

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The pathogenesis of Alzheimer's disease (AD) is now thought to be tightly linked to Aβ 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 Aβ1-42 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.

Original languageEnglish
Pages (from-to)70-76
Number of pages7
JournalMolecular Brain Research
Volume137
Issue number1-2
DOIs
Publication statusPublished - 13-06-2005

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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