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gamma-cleavage-independent functions of presenilin, nicastrin, and aph-1 regulate cell-junction organization and prevent tau toxicity in vivo

  1. Author:
    Doglio, L. E.
    Kanwar, R.
    Jackson, G. R.
    Perez, M.
    Avila, J.
    Dingwal, C.
    Dotti, C. G.
    Fortini, M. E.
    Feiguin, F.

  2. Author Address

    NCI, Canc Res Ctr, Frederick, MD 21702 USA. Univ Turin, Cavalieri Ottolenghi Sci Inst, I-10043 Turin, Italy. Flanders Interuniv Inst Biotechnol VIB, B-3000 Louvain, Belgium. Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. Univ Calif Los Angeles, Dept Neurol, Neurogenet Program, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain. GlaxoSmithKline Pharmaceut, Neurol & GI CEDD, Harlow CM19 5AW, Essex, England Fortini, ME, NCI, Canc Res Ctr, Frederick, MD 21702 USA
    1. Year: 2006
    2. Date: MAY 4
  2. Journal: Neuron
    1. 50
    2. 3
    3. Pages: 359-375
  4. Type of Article: Article
  1. Abstract:

    Genetic analysis of familial Alzheimer's disease has revealed that mutations in the gamma-secretase enzyme presenilin promote toxic A beta secretion; however, presenilin mutations might also influence tau hyperphosphorylation and neurodegeneration through gamma-secretase-independent mechanisms. To address this possibility and determine whether other components of the gamma-secretase complex possess similar regulatory functions, we analyzed the roles of presenilin, nicastrin, and aph-1 in a Drosophila model for tau-induced neurodegeneration. Here, we show that presenilin and nicastrin prevent tau toxicity by modulating the PI3K/Akt/GSK3 beta phosphorylation pathway, whereas aph-1 regulates aPKC/PAR-1 activities. Moreover, we found that these transmembrane proteins differentially regulate the intracellular localization of GSK3 beta and aPKC at cell junctions. Inhibition of gamma-secretase activity neither interfered with these kinase pathways nor induced aberrant tau phosphorylation. These results establish new in vivo molecular functions for the three components of the gamma-secretase complex and reveal a different mechanism that might contribute to neuronal degeneration in Alzheimer's disease

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External Sources

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  2. DOI: 10.1016/j.neuron.2006.03.038
  3. View record in Web of Science®
  4. WOS: 000237726800007

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