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Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. doi: 10.1073/pnas.1713605114. Epub 2017 Oct 9.

Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization.

Zhou R1,2,3, Yang G1,2,3, Shi Y1,2,3,4.

Author information

1
Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; zhour13@mails.tsinghua.edu.cn yanggh@mail.tsinghua.edu.cn shi-lab@tsinghua.edu.cn.
2
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
3
Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
4
Institute of Biology, Westlake Institute for Advanced Study, Xihu District, Hangzhou 310064, Zhejiang Province, China.

Abstract

γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer's disease in an autosomal dominant manner. However, the underlying mechanism of how the mutant PSEN gene may affect the function of the WT allele remains to be elucidated. Here we report that each of the loss-of-function γ-secretase variants that carries a PSEN1 mutation suppresses the protease activity of the WT γ-secretase on Aβ production. Each of these γ-secretase variants forms a stable oligomer with the WT γ-secretase in vitro in the presence of the detergent CHAPSO {3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate}, but not digitonin. Importantly, robust protease activity of γ-secretase is detectable in the presence of CHAPSO, but not digitonin. These experimental observations suggest a dominant negative effect of the γ-secretase, in which the protease activity of WT γ-secretase is suppressed by the loss-of-function γ-secretase variants through hetero-oligomerization. The relevance of this finding to the genesis of Alzheimer's disease is critically evaluated.

KEYWORDS:

Alzheimer’s disease; dominant negative effect; oligomerization; presenilin 1; γ-secretase

Comment in

PMID:
29078389
PMCID:
PMC5715776
DOI:
10.1073/pnas.1713605114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: Y.S. and Y.-M.L. were co-authors on a 2015 paper.

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