γ-Cleavage-Independent Functions of Presenilin, Nicastrin, and Aph-1 Regulate Cell-Junction Organization and Prevent Tau Toxicity In Vivo

نویسندگان

  • Laura E. Doglio
  • Ritu Kanwar
  • George R. Jackson
  • Mar Perez
  • Jesús Avila
  • Colin Dingwall
  • Carlos G. Dotti
  • Mark E. Fortini
  • Fabián Feiguin
چکیده

Genetic analysis of familial Alzheimer's disease has revealed that mutations in the gamma-secretase enzyme presenilin promote toxic Abeta 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/GSK3beta phosphorylation pathway, whereas aph-1 regulates aPKC/PAR-1 activities. Moreover, we found that these transmembrane proteins differentially regulate the intracellular localization of GSK3beta 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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RETRACTED: γ-Cleavage-Independent Functions of Presenilin, Nicastrin, and Aph-1 Regulate Cell-Junction Organization and Prevent Tau Toxicity In Vivo

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عنوان ژورنال:
  • Neuron

دوره 53  شماره 

صفحات  -

تاریخ انتشار 2006