Abstract
Mutations in two genes, presenilin 1 (PS1) and its homologue presenilin 2 (PS2), account for a majority of early onset familial Alzheimer disease cases which are characterized by intracellular neurofibrillary tangles and extracellular amyloid fibrils composed of the amyloid β protein (Aβ). Aß is derived from sequential cleavages of Amyloid Precursor Protein (APP) by ß-secretase and γ-secretase, the latter is composed of four components, PS1, nicastrin (NCT), presenilin enhancer 2 (PEN-2), and anterior pharynx defective (APH-1). These components not only maintain the stability of the γ-secretase complex but also regulate the activity of presenilinase, the protease responsible for the cleavage of full length PS1 into N-terminal and C-terminal fragments (NTF/CTF). We have previously shown that endoproteolysis of PS1 into NTF/CTF by presenilinase requires two critical aspartate residues, suggesting that PS1 may undergo autoproteolysis; full length PS1 complexes with NCT, PEN-2, APH-1 and forms the presenilinase. While these two aspartate residues are necessary for the endoproteolysis of full length PS1, they are equally critical for the γ-secretase cleavage of multiple substrates, and it is hypothesized that the full length PS1/presenilinase is the zymogen of γ-secretase. The inhibition profiles of presenilinase and γ-secretase are illustrated by their biochemical similarity but are pharmacologically distinct. Since the uncleaved PS1 loop may obstruct the entry of γ-secretase substrates to the docking site of the γ-secretase complex, investigation of presenilinase inhibitors interfering with substrate-docking may facilitate a novel approach to identify APP specific γ-secretase inhibitors.
Current Alzheimer Research
Title: From Presenilinase to γ-Secretase, Cleave to Capacitate
Volume: 5 Issue: 2
Author(s): Weiming Xia
Affiliation:
Abstract: Mutations in two genes, presenilin 1 (PS1) and its homologue presenilin 2 (PS2), account for a majority of early onset familial Alzheimer disease cases which are characterized by intracellular neurofibrillary tangles and extracellular amyloid fibrils composed of the amyloid β protein (Aβ). Aß is derived from sequential cleavages of Amyloid Precursor Protein (APP) by ß-secretase and γ-secretase, the latter is composed of four components, PS1, nicastrin (NCT), presenilin enhancer 2 (PEN-2), and anterior pharynx defective (APH-1). These components not only maintain the stability of the γ-secretase complex but also regulate the activity of presenilinase, the protease responsible for the cleavage of full length PS1 into N-terminal and C-terminal fragments (NTF/CTF). We have previously shown that endoproteolysis of PS1 into NTF/CTF by presenilinase requires two critical aspartate residues, suggesting that PS1 may undergo autoproteolysis; full length PS1 complexes with NCT, PEN-2, APH-1 and forms the presenilinase. While these two aspartate residues are necessary for the endoproteolysis of full length PS1, they are equally critical for the γ-secretase cleavage of multiple substrates, and it is hypothesized that the full length PS1/presenilinase is the zymogen of γ-secretase. The inhibition profiles of presenilinase and γ-secretase are illustrated by their biochemical similarity but are pharmacologically distinct. Since the uncleaved PS1 loop may obstruct the entry of γ-secretase substrates to the docking site of the γ-secretase complex, investigation of presenilinase inhibitors interfering with substrate-docking may facilitate a novel approach to identify APP specific γ-secretase inhibitors.
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Cite this article as:
Xia Weiming, From Presenilinase to γ-Secretase, Cleave to Capacitate, Current Alzheimer Research 2008; 5 (2) . https://dx.doi.org/10.2174/156720508783954712
DOI https://dx.doi.org/10.2174/156720508783954712 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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