Review
Presenilin-dependent regulated intramembrane proteolysis and
g-secretase activity
J. V. McCarthy
*
, C. Twomey and P. Wujek
Signal Transduction Laboratory, Biochemistry Department, University College Cork, Cork (Ireland),
Fax : +353-(0) 21-490-1382, e-mail: jv.mccarthy@ucc.ie
Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008
Online First 4 February 2009
Abstract. Inhibiting the production of amyloid-b by
antagonising g-secretase activity is currently being
pursued as a therapeutic strategy for Alzheimers
disease (AD). However, early pre-clinical studies
have demonstrated that disruption of presenilin-
dependent g-secretase alters many presenilin-depend-
ent processes, leading to early lethality in several AD
model organisms. Subsequently, transgenic animal
studies have highlighted several gross developmental
side effects arising from presenilin deficiency. Partial
knockdown or tissue-specific knockout of presenilins
has identified the skin, vascular and immune systems
as very sensitive to loss of presenilin functions. A more
appreciative understanding of presenilin biology is
therefore demanded if g-secretase is to be pursued as a
therapeutic target. Herein we review the current
understanding of g-secretase complexes; their regu-
lation, abundance of interacting partners and diversity
of substrates. We also discuss regulation of the g-
secretase complexes, with an emphasis on the func-
tional role of presenilins in cell biology.
Keywords. Presenilin, g-secretase complexes, regulated intramembrane proteolysis, signal transduction,
Alzheimers disease.
Introduction
The presenilins were initially identified through
genetic linkage of families with autosomal dominant
forms of familial Alzheimers disease (FAD), but have
now emerged as key components of g-secretase
protease associated with all forms of Alzheimers
disease (AD) (reviewed in [1– 4]). Genetic studies of
families with FAD have shown that nearly 50 % of
FAD patients bear mutations in either of the two
presenilin-encoding genes, PSEN1 or PSEN2 [5]. The
PSEN1 and PSEN2 genes encode the ~50kDa pre-
senilin-1 (PS1) and presenilin-2 (PS2) proteins re-
spectively, which are rapidly endoproteolytically
cleaved into active amino- and carboxyl-terminal
fragments (NTF/CTF), which subsequently interact
with each other to form stable heterodimers. Subse-
quent biochemical, molecular and genetic studies
have shown that the presenilins are the catalytic
component of the multiprotein g-secretase enzyme
complexes [6 –8]. Presenilin-dependent cleavage of
amyloid-b (Ab) precursor protein (APP) contributes
to the generation of Ab peptides and the formation of
pathological Ab senile plaques. Mutations in PSEN1
and PSEN2, which contribute to the onset of FAD,
lead to an increase in the generation of the more
amylodiogenic 42 amino acid Ab peptide (Ab
42
). This
shift in Ab
42
abundance, coupled with the fact that
Ab
42
is more amylodiogenic than the predominant
* Corresponding author.
Cell. Mol. Life Sci. 66 (2009) 1534 – 1555
1420-682X/09/091534-22
DOI 10.1007/s00018-009-8435-9
Birkhäuser Verlag, Basel, 2009
Cellular and Molecular Life Sciences