The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Yuichi Hashimoto, Osahiko Tsuji, Kohsuke Kanekura, Sadakazu Aiso, Takako Niikura, Masaaki Matsuoka, Ikuo Nishimoto

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Certain cases of familial Alzheimer's disease are caused by mutants of amyloid-β precursor protein (AβPP), including V642I-AβPP, K595N/M596L-AβPP (NL-AβPP), A617G-AβPP, and L648P-AβPP. By using an unbiased functional screening with transfection and expression of a human brain cDNA library, we searched for genes that protect neuronal cells from toxicity by V642I-AβPP. One protective clone was identical to the human GTX, a neuronal homeobox gene. Human Gtx (hGtx) inhibited caspase inhibitor-sensitive neuronal cell death not only by V642I-AβPP but also by L648P-, NL-, A617G-AβPP, apolipoprotein E4, and Aβ. The region of hGtx responsible for this rescue function was specified to be its homeodomain (Lys148-His207). The rescue function was shared by DLX4, a distal-less family gene with a homeodomain only 38.3% homologous to that of hGtx, suggesting that this function would be generally shared by homeodomains. The neuroprotective function of hGtx was attributable to hGtx-stimulated production and secretion of insulin-like growth factor-I. This study provides molecular clues to understand how neuronal cells developmentally regulate themselves against cell death as well as to develop reagents effective in curative therapeutics of Alzheimer's disease.

Original languageEnglish
Pages (from-to)16767-16777
Number of pages11
JournalJournal of Biological Chemistry
Volume279
Issue number16
DOIs
Publication statusPublished - 2004 Apr 16

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Hashimoto, Y., Tsuji, O., Kanekura, K., Aiso, S., Niikura, T., Matsuoka, M., & Nishimoto, I. (2004). The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain. Journal of Biological Chemistry, 279(16), 16767-16777. https://doi.org/10.1074/jbc.M313630200