title: MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid β precursor protein and presenilins.
abstract: The death of cholinergic neurons in the cerebral cortex and certain subcortical regions is linked to irreversible dementia relevant to AD (Alzheimer's disease). Although multiple studies have shown that expression of a FAD (familial AD)-linked APP (amyloid β precursor protein) or a PS (presenilin) mutant, but not that of wild-type APP or PS, induced neuronal death by activating intracellular death signals, it remains to be addressed how these signals are interrelated and what the key molecule involved in this process is. In the present study, we show that the PS1-mediated (or possibly the PS2-mediated) signal is essential for the APP-mediated death in a γ-secretase-independent manner and vice versa. MOCA (modifier of cell adhesion), which was originally identified as being a PS- and Rac1-binding protein, is a common downstream constituent of these neuronal death signals. Detailed molecular analysis indicates that MOCA is a key molecule of the AD-relevant neuronal death signals that links the PS-mediated death signal with the APP-mediated death signal at a point between Rac1 [or Cdc42 (cell division cycle 42)] and ASK1 (apoptosis signal-regulating kinase 1).
authors: Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors: Nobuyuki
authors: N
authors: Tachi
authors: Yuichi
authors: Y
authors: Hashimoto
authors: Masaaki
authors: M
authors: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides; D053763:Presenilins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D017931:DNA Primers; C485840:DOCK3 protein, human; C410623:Dock3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D053763:Presenilins; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D011994:Recombinant Proteins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein