A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death.
AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.
Kanekura
Kohsuke
K
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Hashimoto
Yuichi
Y
Kita
Yoshiko
Y
Sasabe
Jumpei
J
Aiso
Sadakazu
S
Nishimoto
Ikuo
I
Matsuoka
Masaaki
M
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D006147:Guanine / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000737:chemistry; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D000077191:Wortmannin; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000730:Androstadienes; D004247:DNA; D004791:Enzyme Inhibitors; D020558:GTP Phosphohydrolases; D005978:Glutathione; D005982:Glutathione Transferase; D006147:Guanine; D020662:Guanine Nucleotide Exchange Factors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012685:Sepharose; D013482:Superoxide Dismutase; D000077191:Wortmannin; D020830:rac1 GTP-Binding Protein; C438187:ALS2 protein, human; C494918:AKT1 protein, human