The Gtx homeodomain transcription factor exerts neuroprotection using its homeodomain.
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.
Hashimoto
Yuichi
Y
Departments of Pharmacology and Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
Tsuji
Osahiko
O
Kanekura
Kohsuke
K
Aiso
Sadakazu
S
Niikura
Takako
T
Matsuoka
Masaaki
M
Nishimoto
Ikuo
I
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*
D016564:Amyloid beta-Protein Precursor; C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C425301:NKX6-2 protein, human; D018696:Neuroprotective Agents; D014157:Transcription Factors