title: The Gtx homeodomain transcription factor exerts neuroprotection using its homeodomain.
abstract: Certain cases of familial Alzheimer's disease are caused by mutants of amyloid-beta precursor protein (AbetaPP), including V642I-AbetaPP, K595N/M596L-AbetaPP (NL-AbetaPP), A617G-AbetaPP, and L648P-AbetaPP. 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-AbetaPP. 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-AbetaPP but also by L648P-, NL-, A617G-AbetaPP, apolipoprotein E4, and Abeta. 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.
authors.affiliation: Departments of Pharmacology and Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Osahiko
authors.initials: O
authors.lastname: Tsuji
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Takako
authors.initials: T
authors.lastname: Niikura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C425301:NKX6-2 protein, human; D018696:Neuroprotective Agents; D014157:Transcription Factors