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Identification of new Presenilin‐1 phosphosites: implication for γ‐secretase activity and Aβ production
Author(s) -
Matz Alexandre,
HalamodaKenzaoui Blanka,
Hamelin Romain,
Mosser Sebastien,
Alattia JeanRené,
Dimitrov Mitko,
Moniatte Marc,
Fraering Patrick C.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12996
Subject(s) - presenilin , amyloid precursor protein secretase , amyloid precursor protein , microbiology and biotechnology , biochemistry , phosphorylation , biology , chemistry , protein subunit , alzheimer's disease , gene , disease , medicine , pathology
An important pathological hallmark of Alzheimer's disease ( AD ) is the deposition of amyloid‐beta (Aβ) peptides in the brain parenchyma, leading to neuronal death and impaired learning and memory. The protease γ‐secretase is responsible for the intramembrane proteolysis of the amyloid‐β precursor protein ( APP ), which leads to the production of the toxic Aβ peptides. Thus, an attractive therapeutic strategy to treat AD is the modulation of the γ‐secretase activity, to reduce Aβ42 production. Because phosphorylation of proteins is a post‐translational modification known to modulate the activity of many different enzymes, we used electrospray ( LC ‐ MS / MS ) mass spectrometry to identify new phosphosites on highly purified human γ‐secretase. We identified 11 new single or double phosphosites in two well‐defined domains of Presenilin‐1 ( PS 1), the catalytic subunit of the γ‐secretase complex. Next, mutagenesis and biochemical approaches were used to investigate the role of each phosphosite in the maturation and activity of γ‐secretase. Together, our results suggest that the newly identified phosphorylation sites in PS 1 do not modulate γ‐secretase activity and the production of the Alzheimer's Aβ peptides. Individual PS 1 phosphosites shall probably not be considered therapeutic targets for reducing cerebral Aβ plaque formation in AD .In this study, we identified 11 new phosphosites in Presenilin‐1 (PS1), the catalytic subunit of the Alzheimer's γ‐secretase complex. By combining a mutagenesis approach with cell‐based and cell‐free γ‐secretase assays, we demonstrate that the new phosphosites do not modulate the maturation and activity of γ‐secretase. Individual PS1 phosphosites shall thus not be considered therapeutic targets for reducing cerebral Aβ plaque formation in Alzheimer's Disease. Aβ, amyloid beta.

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