G protein βγ complex-mediated apoptosis by familial Alzheimer's disease mutant of APP

Ugo Giambarella, Tomoki Yamatsuji, Takashi Okamoto, Takashi Matsui, Tsuneya Ikezu, Yoshitake Murayama, Michael A. Levine, Arieh Katz, Narasimhan Gautam, Ikuo Nishimoto

    Research output: Contribution to journalArticlepeer-review

    Abstract

    In familial Alzheimer's disease (FAD), three missense mutations, V642I, V642F and V642G, that co-segregate with the disease phenotype have been discovered in the 695 amino acid form of the amyloid precursor protein APP. Expression of these mutants causes a COS cell NK1 clone to undergo pertussis toxin-sensitive apoptosis in an FAD trait-linked manner by activating the G protein G0, which consists of Gα0, and Gβγ subunits. We investigated which subunit was responsible for the induction of apoptosis by V642I APP in NK1 cells. In the same system, expression of mutationally activated Gα0, or Gα(i) induced little apoptosis. Apoptosis by V642I APP was antagonized by the overexpression of the carboxy-terminal amino acids 495-689 of the β-adrenergic receptor kinase-l, which blocks the specific functions of Gβγ. Co-transfection of Gβ2γ2 cDNAs, but not that of other Gβxγz (x = 1-3; z = 2, 3), induced DNA fragmentation in a manner sensitive to bcl-2. These data implicate Gβγ as a cell death mediator for the FAD-associated mutant of APP.

    Original languageEnglish (US)
    Pages (from-to)4897-4907
    Number of pages11
    JournalThe EMBO journal
    Volume16
    Issue number16
    DOIs
    StatePublished - Aug 15 1997

    Keywords

    • βγ complex
    • Amyloid precursor protein
    • Apoptosis
    • Familial Alzheimer's disease
    • G protein

    ASJC Scopus subject areas

    • Genetics
    • Cell Biology

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