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J Biol Chem, Vol. 273, Issue 6, 3205-3211, February 6, 1998
From the Mutations in the presenilin (PS) genes are linked
to early onset familial Alzheimer's disease (FAD). PS-1 proteins are
proteolytically processed by an unknown protease to two stable
fragments of ~30 kDa (N-terminal fragment (NTF)) and ~20 kDa
(C-terminal fragment (CTF)) (Thinakaran, G., Borchelt, D. R., Lee,
M. K., Slunt, H. H., Spitzer, L., Kim, G., Ratovitsky, T.,
Davenport, F., Nordstedt, C., Seeger, M., Hardy, J., Levey, A. I.,
Gandy, S. E., Jenkins, N. A., Copeland, N. G., Price,
D. L., and Sisodia, S. S. (1996) Neuron 17, 181-190). Here we show that the CTF and NTF of PS-1 bind to each
other. Fractionating proteins from
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid-extracted membrane preparations by velocity sedimentation reveal a high molecular mass SDS and Triton X-100-sensitive complex of
approximately 100-150 kDa. To prove if both proteolytic fragments of
PS-1 are bound to the same complex, we performed
co-immunoprecipitations using multiple antibodies specific to the CTF
and NTF of PS-1. These experiments revealed that both fragments of PS-1
occur as a tightly bound non-covalent complex. Upon overexpression,
unclipped wild type PS-1 sediments at a lower molecular weight in
glycerol velocity gradients than the endogenous fragments. In contrast, the non-cleavable, FAD-associated PS-1 Most cases of Alzheimer's disease
(AD)1 occur sporadically,
with a strong increase in risk during aging (for review see Ref. 5).
However, in at least 10-15% of cases, autosomal dominant mutations
have been found to cause early onset familial AD (FAD). Mutations in
three genes are known so far to cause FAD. Mutations within the gene
encoding the Two highly homologous PS proteins (PS-1 and PS-2) are known (Refs.
16-18; for review see Refs. 20 and 21). PS-1 and PS-2 are
membrane-bound proteins with 7 or 8 transmembrane (TM) domains (22).
Mutations accumulate within the TM domains but are also frequently
found within the hydrophilic domains, specifically the large
cytoplasmic loop between TM6 and putative TM7 (22; for review see Refs.
19-21).
Based on the results from genetic rescue experiments of the mutant PS
homologue (the sel-12 gene (23)) in Caenorhabditis elegans and gene deletions in mice, PS-1 is most likely involved in cell fate decisions via the Notch signaling pathway (2, 3, 24, 25). In C. elegans, wild type human PS-1 and PS-2 were found to rescue all aspects of the sel-12 mutant
phenotype (2, 3). The sel-12 gene is known to facilitate
Notch signaling (23); therefore, the results from the rescue
experiments strongly suggest that human PS proteins play an important
role in the Notch signaling cascade of vertebrates as well.
This conclusion was further supported when knock-outs of the PS-1 gene
were generated in mice, since the loss of PS-1 expression resulted in a
phenotype reminiscent of Notch knock-outs (24, 25).
Surprisingly, all FAD-associated point mutations of PS-1 tested so far
exhibited a strongly reduced ability to rescue the sel-12
mutant phenotype in C. elegans (2, 3), indicating that
theses mutations might change functionally important amino acids (23).
This notion is supported by the finding that FAD-associated mutations
occur at positions that are highly conserved during evolution in all PS
genes analyzed so far (for review, see Ref. 21). In contrast, expression of PS-1 lacking exon 9 due to a naturally occurring FAD
causing splicing mutation (26) rescued the sel-12 mutant phenotype surprisingly well (Refs. 2 and 3; also see below).
Interestingly, PS proteins have been found to occur predominantly as
stable C-terminal and N-terminal fragments (CTF and NTF; see Fig. 1),
whereas only low levels of unclipped PS holoprotein can be detected
within all cell lines and tissues analyzed to date (1, 27, 28).
Surprisingly, mutations within the TM domains of the PS-1 NTF appear to
result not only in the hyperaccumulation of the NTF by itself but also
in the accumulation of the complementary CTF (4). Because it is highly
unlikely that mutations that occur far away from the cleavage site (28)
of PS-1 directly influence the rate of cleavage, other mechanisms
allowing the accumulation of both fragments in a stoichiometrically
regulated manner must be considered. In this regard, it is interesting
to note that overexpression of PS proteins does not result in a linear increase of fragment formation (1, 28). Moreover, expression of the
Cell Culture--
K293 cells were cultured in Dulbecco's
minimal essential medium (Glutamax1; Life Technologies, Inc.)
supplemented with 10% fetal calf serum and 1% penicillin/streptomycin
(30). K293 cells stably transfected with wt PS-1 or the Isolation of Membrane Proteins--
Kidney 293 cells were grown
to confluence. Cells of 10 10-cm dishes were scraped in
phosphate-buffered saline and pelleted. The cell pellet was washed
three times in phosphate-buffered saline. Cells were then resuspended
in 5 ml of RSB buffer (10 mM Tris, pH 7.5, 20 mM KCl, 1.5 mM MgAc2) containing
protease inhibitors as described (30) and homogenized with 30 strokes
in a glass Dounce homogenizer. To prepare a postnuclear supernatant,
the homogenate was centrifuged at 1000 × g for 15 min
at 4 °C. Membranes from the postnuclear supernatant were then
pelleted by centrifugation for 1 h at 100,000 × g
at 4 °C. Membranes were washed in a high salt HEPES buffer (1 M KCl, 20 mM HEPES, pH 7.2, 2 mM
EGTA, 2 mM EDTA, 2 mM DTT) containing protease
inhibitors (30). The purified membranes were extracted with 2% CHAPS
in HEPES buffer (100 mM KCl, 20 mM HEPES pH
7.2, 2 mM EGTA, 2 mM EDTA, 2 mM
DTT, containing protease inhibitors as described (30)) for 1 h on ice. Alternatively, proteins were also extracted with 1% Triton X-100
or 0.5% SDS in HEPES buffer. For SDS extraction, K+ was
substituted by Na+ in the HEPES buffer. Membrane extracts
were cleared by ultracentrifugation for 1 h at 100,000 × g at 4 °C. Protein concentrations were determined by
Bio-Rad assay.
Glycerol Velocity Gradients--
Glycerol velocity gradient
centrifugation was performed as described by Hay et al.
(31). Briefly, 1-2 mg of membrane proteins were loaded on a linear
5-25% (v/v) glycerol velocity gradient (31) in gradient buffer (100 mM KCl, 20 mM HEPES, pH 7.2, 2 mM
EGTA, 2 mM EDTA, 2 mM DTT, 0.2% CHAPS).
Gradients were centrifuged at 40,000 rpm for 16 h at 4 °C in a
SW40 rotor (Beckman L-70 ultracentrifuge). After centrifugation, 13 fractions of 1 ml were collected from bottom to top. Proteins were
precipitated with an equal volume of 20% trichloroacetic acid, and the
precipitated proteins were washed with 90% acetone. Protein pellets
were solubilized in sample buffer containing 4 M urea and
incubated for 10 min at 65 °C (32). Proteins were separated on
SDS-urea gels (32) and transferred to polyvinylidene difluoride
membranes.
Antibodies--
The polyclonal antibodies, 2953 and 3027, used
in this study were described previously (29, 32). The monoclonal
antibody PS1N to the N terminus of PS-1 is described by Capell et
al. (33). The monoclonal antibody APS 18 to the large loop of PS-1
was raised to a peptide corresponding to amino acids 314-334 of PS-1.
Epitopes of all antibodies used are indicated in Fig. 1.
Immunoblotting--
Immunoblotting was carried out as described
(32). Bound antibodies were detected by enhanced chemiluminescence
(Amersham Corp.) or the ECL-PLUS system (Amersham Corp.).
Co-immunoprecipitations--
For co-immunoprecipitation,
membranes were prepared as described above and extracted either with
2% CHAPS, 1% Triton X-100, or 0.5% SDS. For SDS extraction,
K+ was substituted by Na+ in the HEPES buffer.
To remove undissolved membrane fragments, the extracts were pelleted by
ultracentrifugation for 1 h at 100,000 × g at
4 °C. Incubation with PS-1 antibodies was performed as described
(29, 32). SDS extracts were diluted 10 × prior to antibody
addition; CHAPS and Triton X-100 extracts were immunoprecipitated without further dilution. Immunoprecipitations of CHAPS-extracted proteins were washed 4 × for 20 min in CHAPS washing buffer
(0.5% CHAPS, 200 mM NaCl, 50 mM HEPES, pH
7.6). Immunoprecipitations of SDS-extracted proteins were washed as
described (30). Immunoprecipitations of Triton X-100-extracted proteins
were washed 4 × for 20 min in STEN buffer only (30).
To determine whether PS-1 fragments occur as a complex, we
analyzed membrane protein fractions from human K293 cells. In most experiments, we specifically used untransfected K293 cells to allow the
analysis of endogenous PS proteins under in vivo conditions. Moreover, this cell line is highly appropriate for the analysis of the
biochemistry of the FAD-associated proteins ( Identification of a Presenilin Complex--
Membrane preparations
from K293 cells were extracted with CHAPS, and the proteins were
separated on a continuous 5-25% glycerol velocity gradient as
described previously (31). To determine the apparent molecular weight
of isolated proteins, molecular mass markers of 29-205 kDa were
separated on parallel gradients (Fig. 2A). Gradients were
fractionated and proteins precipitated with trichloroacetic acid. An
aliquot of each fraction was then analyzed by immunoblotting using
antibodies to the C and N termini of PS-1 (epitopes of all antibodies
used are indicated in Fig. 1). Antibody
3027 to the large loop of PS-1 (29) detected a prominent, approximately
20-kDa CTF (Fig. 2C). In
addition to the 20-kDa CTF, we also consistently found smaller amounts
of a CTF of 23 kDa (labeled with an asterisk in Fig.
2C), which corresponds to the previously described protein
kinase C/protein kinase A-phosphorylated form of the PS-1 20-kDa CTF
(29, 36). The majority of the CTF accumulated at an apparent molecular
mass of approximately 100-150 kDa in fractions 7-11 of the glycerol
velocity gradient (Fig. 2, A-C). It should be noted that
the sedimentation velocity not only depends on the molecular weight but
also on the density of the complex. Therefore, we cannot rule out that
the PS-1 complex could be of much higher molecular weight in
vivo. In addition to a major peak at 100-150 kDa, we also
detected slightly variable minor amounts of the CTF in the first
fractions of the low molecular weight range (Fig. 2, B and
C). It should be noted that in all experiments no PS-1
fragments were detected in the pellet of the glycerol velocity
gradients.
The Proteolytic Fragments of the Alzheimer's Disease-associated
Presenilin-1 Form Heterodimers and Occur as a 100-150-kDa Molecular
Mass Complex*
,,,
,**
Central Institute of Mental Health, New York University
Medical Center, Department of Psychiatry,
Orangeburg, New York 10962
ABSTRACT
Top
Abstract
Introduction
Procedures
Results
Discussion
References
exon 9 sediments at a molecular weight similar to that observed for the endogenous
proteolytic fragments. This result may indicate that the exon 9 mutation generates a mutant protein that exhibits biophysical
properties similar to the naturally occurring PS-1 fragments. This
could explain the surprising finding that the exon 9 mutation is
functionally active, although it cannot be proteolytically processed
(Baumeister, R., Leimer, U., Zweckbronner, I., Jakubek, C.,
Grünberg, J., and Haass, C. (1997) Genes & Function
1, 149-159; Levitan, D., Doyle, T., Brousseau, D., Lee, M.,
Thinakaran, G., Slunt, H., Sisodia, S., and Greenwald, I. (1996)
Proc. Natl. Acad. Sci. U. S. A. 93, 14940-14944).
Formation of a high molecular weight complex of PS-1 composed of both
endogenous PS-1 fragments may also explain the recent finding that
FAD-associated mutations within the N-terminal portion of PS-1 result
in the hyperaccumulation not only of the NTF but also of the CTF (Lee,
M. K., Borchelt, D. R., Kim, G., Thinakaran, G., Slunt, H. H., Ratovitski, T., Martin, L. J., Kittur, A., Gandy, S., Levey,
A. I., Jenkins, N., Copeland, N., Price, D. L., and Sisodia, S. S. (1997) Nat. Med. 3, 756-760). Moreover, these results
provide a model to understand the highly regulated expression and
processing of PS proteins.
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References
-amyloid precursor protein (APP) all cause the
enhanced production of the 42-amino acid version of the amyloid
-peptide (A42; see Ref. 6; for review, see Ref. 5). A42 is a
major component of amyloid plaques (7), which are the pathological
hallmark of the disease (5). A42 exhibits enhanced neurotoxicity,
which might be due to its increased ability to form insoluble fibers
(8, 9). Increased production of A42 (10-15) was also found to
result from the much more common mutations within the presenilin (PS)
genes (16-18). Since mutations within the PS genes are responsible for
many FAD cases, the analysis of the cellular biology of these proteins
will undoubtedly lead to a better understanding of the molecular
mechanisms involved in AD (19).
exon 9 mutation (26), which is known to inhibit conventional proteolytic processing of PS-1, also markedly decreases the formation of the endogenous PS fragments (1, 4, 29). These results indicate a
highly regulated mechanism that allows the accumulation of only certain
levels of both fragments. Any disturbance in this regulation, such as
hyperaccumulation of the PS fragments or of the unclipped PS-1 exon
9 protein (4), appears to be associated with early onset FAD, probably
due to the enhanced production of A42. However, nothing is known
about the nature of the regulation mechanism. We have therefore
analyzed whether PS-1 fragments interact with each other. We find that
the NTF of PS-1 co-immunoprecipitates with the CTF. Moreover, both
fragments form a 100-150-kDa complex in untransfected cells. Binding
of PS fragments might therefore explain their concomitant accumulation
in transgenic animals expressing mutations within the N-terminal
portion of the PS protein. These results might also suggest that the
highly regulated fragment formation could be due to the formation of a
stoichiometric high molecular weight complex.
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References
exon 9 mutation were described previously (13).
RESULTS
Top
Abstract
Introduction
Procedures
Results
Discussion
References
APP and PS-1/PS-2), since APP metabolism and the effects of APP and PS mutations originally sorted out in K293 cells (13, 30, 34, 35) and other
peripheral cell lines such as COS (15) and CHO (14) were completely
confirmed in neuronal cells, primary cell cultures, human and mouse
brain tissue, cerebrospinal fluid, and plasma (10-13, 15, 35).
View larger version (23K):
[in a new window]
Fig. 1.
Schematic representation of PS-1 and its
proteolytic processing. Bars indicate the epitopes of
polyclonal antibodies (2953, 3027) used in this study.
Arrows indicate the epitopes of monoclonal antibodies (PS1N,
APS18). Black box = exon 9 (which encodes the site for
proteolytic cleavage of PS-1). The cleavage site is indicated by an
arrowhead. Numbers at the C terminus of the NTF indicate the
heterogeneous cleavage sites after amino acids 291, 292, and 298 (28).
View larger version (33K):
[in a new window]
Fig. 2.
N- and C-terminal fragments of PS-1 form a
100-150-kDa complex. A, CHAPS-extracted membrane proteins
were separated on linear 5-25% glycerol velocity gradients. Protein
concentrations (% total protein/fraction) and glycerol concentrations
are shown. The sedimentation of molecular mass markers is shown below
the concentration profiles. B, sedimentation profile of the
PS-1 NTF and CTF in a linear 5-25% glycerol velocity gradient.
Shorter exposures of the immunoblots shown in C and
D were scanned, and the relative amounts of the
corresponding protein are shown. C, sedimentation of the
PS-1 CTF in a 5-25% glycerol velocity gradient. The endogenous PS-1
CTF was detected with antibody 3027. *, CTF phosphorylated by protein
kinase C/protein kinase A (29, 36). D, sedimentation of the
PS-1 NTF in a 5-25% glycerol velocity gradient. The endogenous PS-1
NTF was detected with antibody PS1N.
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Co-immunoprecipitation of the NTF and CTF of PS-1-- The co-sedimentation of both fragments within the same fractions raised the possibility that the PS fragments interact with each other. To prove this is indeed the case, we performed co-immunoprecipitation studies. Isolated membranes from K293 cells were extracted with 2% CHAPS. Identical aliquots of the extract were immunoprecipitated either with antibody 2953 to the N terminus of PS-1 or antibody 3027 to the C terminus of PS-1. Immunoprecipitates were separated on 11% SDS-urea gels and immunoblotted with the monoclonal antibody, APS18, to the large loop of PS-1. Interestingly, the monoclonal antibody detected the CTF not only after immunoprecipitation with antibody 3027 but also after immunoprecipitation with antibody 2953 to the N terminus (Fig. 5A). This finding clearly indicates that the NTF interacts with the CTF under in vivo conditions in untransfected cells. To confirm this more rigorously, the converse experiment was performed. CHAPS-extracted membrane preparations were immunoprecipitated with the same antibodies but immunoblotted with the monoclonal antibody PS1N to the N-terminal domain of PS-1. Again, co-immunoprecipitation of both PS fragments was observed, as indicated by the detection of the NTF after immunoprecipitation with antibody 3027 to the large loop of PS-1 (Fig. 5B). Taken together, these data indicate that the NTF and CTF of PS-1 interact in untransfected cells.
|
Mutant PS-1 with the Exon 9 Deletion but Not Wild Type
Full-length PS-1 Forms a Complex Similar to the Endogenous
Fragments--
Consistent with previously reported results (1, 29), we
could not detect the endogenous, unclipped full-length form of PS-1 in
untransfected K293 cells (data not shown). To determine if unclipped
PS-1 can participate in PS complex formation, we analyzed membrane
preparations from K293 cells stably overexpressing wt PS-1 (13) on the
5-25% glycerol velocity gradients. Although the PS-1 fragments were
predominantly detected in fractions 7-11 (see above), the unclipped
PS-1 holoprotein sedimented at a lower molecular weight range in
fractions 3-8 (Fig. 6, A and
B).
|
exon 9 mutation (26) and analyzed the sedimentation of this truncated, unclipped mutant PS-1 in the glycerol velocity gradients. Surprisingly, we found that this uncleavable form of PS-1 accumulated in high molecular fractions (fractions 7-12 in Fig. 6, A
and C). It therefore appears that PS-1 with the exon 9 deletion is able to form a 100-150-kDa complex similar to the
endogenous PS-1 fragments.
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DISCUSSION |
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Abstract
Introduction
Procedures
Results
Discussion
References
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The data presented here strongly indicate that endogenous PS-1
fragments interact with each other and form a 100-150-kDa complex in
untransfected cells. Binding of PS-1 fragments is supported by multiple
co-immunoprecipitation experiments using C-terminal antibodies for the
detection of the NTF and N-terminal antibodies for the detection of the
CTF. Co-migration of the NTF and CTF in glycerol velocity gradients
supports these results. Moreover, both fragments were
co-immunoprecipitated from the peak fractions of the glycerol velocity
gradients. Binding of the PS fragments was also independently
observed.2 The separation of
APP from PS-1 fragments within the same glycerol velocity gradient
(data not shown) rules against nonspecific aggregation of the
endogenous PS-1 fragments. Furthermore, the overexpressed highly
hydrophobic wt PS-1 holoprotein sediments at lower molecular weight
than the endogenous fragments, whereas overexpression of exon 9 PS-1
resulted in a sedimentation more similar to that of the endogenous
fragments. These results make it highly unlikely that the observed PS
complexes are due to artifactual aggregation, because that would be
expected to be more likely after overexpression of PS proteins (32).
Moreover, our data are also consistent with the previous finding that
the CTF of PS-1 may oligomerize (36). PS-1 fragments are bound most
likely by non-covalent interactions. The sensitivity of the interaction
to SDS and Triton but not DTT suggests that PS-1 fragments bind via
hydrophobic interactions, making it likely that the trans-membrane
domains are involved.
PS proteins predominantly occur as proteolytic fragments in all tissues
and cell lines analyzed so far (1, 27, 28). These fragments appear to
play an important role in causing early onset FAD. The natural
occurring exon 9 mutation (26), which abolished proteolytic cleavage
(1), results in early onset FAD probably related to the accumulation of
unclipped PS-1 molecules (1, 4). Moreover, in transgenic mice, the
expression of two mutations within the N-terminal domain of PS-1 can
result in the hyperaccumulation of PS-1 fragments (4). It therefore appears that subtle changes in a normally highly balanced fragment formation could result in early onset FAD. To prevent excess fragment formation, a natural occurring control mechanism appears to inhibit any
marked overproduction or accumulation of PS fragments. Upon overexpression of PS-1 or PS-2 in transfected cells or transgenic mice,
only a very small increase of fragment amounts is observed (1).
Interestingly, it was found that overexpression of PS-1 results in a
replacement of the endogenous PS-1 fragments by the exogenous fragments
(1). These findings indicate a highly regulated biological mechanism
that leads to balanced fragment formation.
Based on our current results it appears possible that NTF·CTF complex formation could play a role in regulated fragment generation and accumulation. Binding of PS fragments could now explain the coordinate hyperaccumulation of PS fragments in mice expressing some mutant PS genes (4). The mutations used for the latter study occur within a TM domain far away from the recognition site of the PS cleaving enzyme in the large cytoplasmic loop. This makes it unlikely that the mutations influence the rate of precursor cleavage to cause a parallel accumulation of the CTF and the NTF. This apparent paradox may now be explained by our finding that the PS-1 fragments are bound to each other. If, for example, the turnover of a mutant NTF is slowed, the complementary wt CTF would also be stabilized. Binding of PS fragments to a high molecular weight complex might thus play a role in regulation of fragment formation. If one assumes a stoichiometrically defined PS complex containing PS fragments and perhaps other binding partners as well, only a limited number of PS heterodimers could bind. It might be possible that unbound PS fragments and full-length PS-1 are then rapidly removed by proteolytic degradation. This hypothesis is supported by recent findings demonstrating that multiple proteolytic pathways are involved in the degradation of full-length PS and its proteolytic fragments (Refs. 37-40; for review see Refs. 20 and 21).
Further purification of the PS-containing 100-150-kDa complex might
result in the identification of other binding proteins playing a
functional role in the PS-1 complex. Attempts to identify metabolically
labeled binding partners, which may co-immunoprecipitate with PS
fragments, led to a very surprising result. Even after extended
labeling periods, only very minor amounts of the de novo synthesized PS fragments assembled into the complex. Most of the de novo synthesized PS fragments were detected in the low
molecular weight fractions of the glycerol velocity gradients. As
described above the "free" fragments might be rapidly degraded,
whereas PS fragments bound to the complex appear to be stable over very long periods.3 Nevertheless,
one of the most obvious binding proteins might be APP. Indeed it was
reported previously that PS-1 (41, 42) and PS-2 (42) can bind to
APP. However, Thinakaran and Sisodia2 could not confirm
co-immunoprecipitation of PS-1/-2 with APP. Separation of APP
from endogenous PS-1 fragments in glycerol velocity gradients (data not
shown) might indicate that only very small amounts of APP can bind
to PS. However, this could still be in agreement with a transient
binding of very small amounts of APP to PS during its transport to
the cell surface. Beside APP, PS-2 itself might form a complex with
PS-1. Other possible binding partners include members of the
Notch signaling pathway, such as proteins of the Armadillo
family (43). Due to the tissue-specific expression of proteins
belonging to the Armadillo family (43), one might propose the presence
of heterogeneous PS complexes containing a variety of different binding
partners depending on the tissue analyzed. In that regard it is
interesting to note that the Drosophila Notch protein
undergoes proteolytic processing resulting in defined N-terminal and
C-terminal fragments (44, 45), and the fragments are tightly bound to
each other. Moreover, only the proteolytic fragments appear to be
biologically active in Notch signaling (44, 45). It is therefore
tempting to speculate that PS proteins also require proteolytic
cleavage for their biological activity. Furthermore, PS proteins are
believed to be involved in Notch signaling (2, 3, 23-25), which could
indicate a common mechanism of biological activation for at least some
members of the Notch signaling pathway. However, how does one explain
the surprising result that PS-1 with the exon 9 mutation rescues the
mutant sel-12 phenotype well even though it cannot undergo
proteolytic cleavage (2, 3)? One explanation could be that the
unclipped exon 9 PS-1 can form a PS-1 complex similar to the
endogenous fragments, whereas full-length wt PS-1 forms a lower
molecular weight complex. The lack of the domain encoded by exon 9 might mimic a clipped PS-1 molecule, thus allowing complex formation. This is further supported by the finding that expression of PS-1 exon 9 causes a reduction of the endogenous PS fragment formation (1, 4, 29). This is also observed in the high molecular weight fraction
of the glycerol velocity gradients (data not shown), thus indicating
that PS-1 exon 9 behaves like the natural NTF·CTF complex.
Based on our data, we would therefore postulate a stoichiometrically
defined PS complex to be required for the biological as well as the
pathological functions of presenilins, a hypothesis supported by the
recent finding that expression of a recombinant mutant NTF of PS-1 or
PS-2 is not sufficient for overproduction of
A42.4,5
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ACKNOWLEDGEMENT |
|---|
We thank Dr. Tobias Hartmann for the help with quantitation of immunoblots and Theresia Knöbel de Ledezma for technical assistance and Jochen Walter and Harald Steiner for discussion.
| |
FOOTNOTES |
|---|
* This work was supported by Grant SFB317 from the Deutsche Forschungsgemeinschaft (to C. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Central Institute of Mental Health, Dept. of Molecular Biology, J5, 68159 Mannheim, Germany. Tel.: 49-621-1703 884; Fax: 49-621-23429; E-mail: haass{at}as200.zi-mannheim.de.
1
The abbreviations used are: AD, Alzheimer's
disease; A, amyloid -peptide; APP, -amyloid precursor
protein; CTF, C-terminal fragment; FAD, familial Alzheimer's disease;
NTF, N-terminal fragment; PS, presenilin; TM, trans-membrane domain;
CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid;
DTT, dithiothreitol; wt, wild type.
2 G. Thinakaran and S. S. Sisodia, personal communication.
3 A. Capell, H. Steiner, and C. Haass, manuscript in preparation.
4 M. Citron and D. J. Selkoe, personal communications.
5 T. Iwatsubo, personal communication.
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Abstract
Introduction
Procedures
Results
Discussion
References
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H. Steiner, E. Winkler, D. Edbauer, S. Prokop, G. Basset, A. Yamasaki, M. Kostka, and C. Haass PEN-2 Is an Integral Component of the gamma -Secretase Complex Required for Coordinated Expression of Presenilin and Nicastrin J. Biol. Chem., October 11, 2002; 277(42): 39062 - 39065. [Abstract] [Full Text] [PDF]
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 Y.-H. Suh and F. Checler Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease Pharmacol. Rev., September 1, 2002; 54(3): 469 - 525. [Abstract] [Full Text] [PDF]
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G. Tian, C. D. Sobotka-Briner, J. Zysk, X. Liu, C. Birr, M. A. Sylvester, P. D. Edwards, C. D. Scott, and B. D. Greenberg Linear Non-competitive Inhibition of Solubilized Human gamma -Secretase by Pepstatin A Methylester, L685458, Sulfonamides, and Benzodiazepines J. Biol. Chem., August 23, 2002; 277(35): 31499 - 31505. [Abstract] [Full Text] [PDF]
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 C. Kaether, S. Lammich, D. Edbauer, M. Ertl, J. Rietdorf, A. Capell, H. Steiner, and C. Haass Presenilin-1 affects trafficking and processing of {beta}APP and is targeted in a complex with nicastrin to the plasma membrane J. Cell Biol., August 5, 2002; 158(3): 551 - 561. [Abstract] [Full Text] [PDF]
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D.-S. Yang, A. Tandon, F. Chen, G. Yu, H. Yu, S. Arawaka, H. Hasegawa, M. Duthie, S. D. Schmidt, T. V. Ramabhadran, et al. Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins J. Biol. Chem., July 26, 2002; 277(31): 28135 - 28142. [Abstract] [Full Text] [PDF]
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 D. Edbauer, E. Winkler, C. Haass, and H. Steiner Presenilin and nicastrin regulate each other and determine amyloid beta -peptide production via complex formation PNAS, June 25, 2002; 99(13): 8666 - 8671. [Abstract] [Full Text] [PDF]
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J. T. Huse, K. Liu, D. S. Pijak, D. Carlin, V. M.-Y. Lee, and R. W. Doms beta -Secretase Processing in the Trans-Golgi Network Preferentially Generates Truncated Amyloid Species That Accumulate in Alzheimer's Disease Brain J. Biol. Chem., May 3, 2002; 277(18): 16278 - 16284. [Abstract] [Full Text] [PDF]
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Y. Morohashi, N. Hatano, S. Ohya, R. Takikawa, T. Watabiki, N. Takasugi, Y. Imaizumi, T. Tomita, and T. Iwatsubo Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4 J. Biol. Chem., April 19, 2002; 277(17): 14965 - 14975. [Abstract] [Full Text] [PDF]
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W. P. Esler, W. T. Kimberly, B. L. Ostaszewski, W. Ye, T. S. Diehl, D. J. Selkoe, and M. S. Wolfe Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate PNAS, February 20, 2002; (2002) 52436599. [Abstract] [Full Text] [PDF]
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S.-H. Kim, J. Y. Leem, J. J. Lah, H. H. Slunt, A. I. Levey, G. Thinakaran, and S. S. Sisodia Multiple Effects of Aspartate Mutant Presenilin 1 on the Processing and Trafficking of Amyloid Precursor Protein J. Biol. Chem., November 9, 2001; 276(46): 43343 - 43350. [Abstract] [Full Text] [PDF]
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D. Levitan, J. Lee, L. Song, R. Manning, G. Wong, E. Parker, and L. Zhang PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling PNAS, September 26, 2001; (2001) 211321898. [Abstract] [Full Text] [PDF]
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W. P. Esler and M. S. Wolfe A Portrait of Alzheimer Secretases--New Features and Familiar Faces Science, August 24, 2001; 293(5534): 1449 - 1454. [Abstract] [Full Text] [PDF]
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 D. M. A. Mann, S. M. Pickering-Brown, A. Takeuchi, and T. Iwatsubo Amyloid Angiopathy and Variability in Amyloid {beta} Deposition Is Determined by Mutation Position in Presenilin-1-Linked Alzheimer's Disease Am. J. Pathol., June 1, 2001; 158(6): 2165 - 2175. [Abstract] [Full Text] [PDF]
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 D. J. Selkoe Alzheimer's Disease: Genes, Proteins, and Therapy Physiol Rev, April 1, 2001; 81(2): 741 - 766. [Abstract] [Full Text] [PDF]
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G. Pigino, A. Pelsman, H. Mori, and J. Busciglio Presenilin-1 Mutations Reduce Cytoskeletal Association, Deregulate Neurite Growth, and Potentiate Neuronal Dystrophy and Tau Phosphorylation J. Neurosci., February 1, 2001; 21(3): 834 - 842. [Abstract] [Full Text] [PDF]
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W. Xia, W. J. Ray, B. L. Ostaszewski, T. Rahmati, W. T. Kimberly, M. S. Wolfe, J. Zhang, A. M. Goate, and D. J. Selkoe Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta -protein generation PNAS, August 1, 2000; 97(16): 9299 - 9304. [Abstract] [Full Text] [PDF]
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K. Shirotani, K. Takahashi, W. Araki, K. Maruyama, and T. Tabira Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function J. Biol. Chem., February 4, 2000; 275(5): 3681 - 3686. [Abstract] [Full Text] [PDF]
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T. Tomita, R. Takikawa, A. Koyama, Y. Morohashi, N. Takasugi, T. C. Saido, K. Maruyama, and T. Iwatsubo C Terminus of Presenilin Is Required for Overproduction of Amyloidogenic Abeta 42 through Stabilization and Endoproteolysis of Presenilin J. Neurosci., December 15, 1999; 19(24): 10627 - 10634. [Abstract] [Full Text] [PDF]
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H. Jacobsen, D. Reinhardt, M. Brockhaus, D. Bur, C. Kocyba, H. Kurt, M. G. Grim, R. Baumeister, and H. Loetscher The Influence of Endoproteolytic Processing of Familial Alzheimer's Disease Presenilin 2 on Abeta 42 Amyloid Peptide Formation J. Biol. Chem., December 3, 1999; 274(49): 35233 - 35239. [Abstract] [Full Text] [PDF]
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W. G. Annaert, L. Levesque, K. Craessaerts, I. Dierinck, G. Snellings, D. Westaway, P. St. George-Hyslop, B. Cordell, P. Fraser, and B. De Strooper Presenilin 1 Controls {gamma}-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons J. Cell Biol., October 18, 1999; 147(2): 277 - 294. [Abstract] [Full Text] [PDF]
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I. Imafuku, T. Masaki, M. Waragai, S. Takeuchi, M. Kawabata, S.-i. Hirai, S. Ohno, L.E. Nee, C.F. Lippa, I. Kanazawa, et al. Presenilin 1 Suppresses the Function of c-Jun Homodimers via Interaction with QM/Jif-1 J. Cell Biol., October 4, 1999; 147(1): 121 - 134. [Abstract] [Full Text] [PDF]
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D. E. Kang, S. Soriano, M. P. Frosch, T. Collins, S. Naruse, S. S. Sisodia, G. Leibowitz, F. Levine, and E. H. Koo Presenilin 1 Facilitates the Constitutive Turnover of beta -Catenin: Differential Activity of Alzheimer's Disease-Linked PS1 Mutants in the beta -Catenin-Signaling Pathway J. Neurosci., June 1, 1999; 19(11): 4229 - 4237. [Abstract] [Full Text] [PDF]
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C. A. Saura, T. Tomita, F. Davenport, C. L. Harris, T. Iwatsubo, and G. Thinakaran Evidence That Intramolecular Associations between Presenilin Domains Are Obligatory for Endoproteolytic Processing J. Biol. Chem., May 14, 1999; 274(20): 13818 - 13823. [Abstract] [Full Text] [PDF]
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B. Stahl, A. Diehlmann, and T. C. Sudhof Direct Interaction of Alzheimer's Disease-related Presenilin 1 with Armadillo Protein p0071 J. Biol. Chem., April 2, 1999; 274(14): 9141 - 9148. [Abstract] [Full Text] [PDF]
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H. Steiner, H. Romig, M. G. Grim, U. Philipp, B. Pesold, M. Citron, R. Baumeister, and C. Haass The Biological and Pathological Function of the Presenilin-1 Delta Exon 9 Mutation Is Independent of Its Defect to Undergo Proteolytic Processing J. Biol. Chem., March 19, 1999; 274(12): 7615 - 7618. [Abstract] [Full Text] [PDF]
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W. J. Ray, M. Yao, P. Nowotny, J. Mumm, W. Zhang, J. Y. Wu, R. Kopan, and A. M. Goate Evidence for a physical interaction between presenilin and Notch PNAS, March 16, 1999; 96(6): 3263 - 3268. [Abstract] [Full Text] [PDF]
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G. Tesco, T.-W. Kim, A. Diehlmann, K. Beyreuther, and R. E. Tanzi Abrogation of the Presenilin 1/beta -Catenin Interaction and Preservation of the Heterodimeric Presenilin 1 Complex following Caspase Activation J. Biol. Chem., December 18, 1998; 273(51): 33909 - 33914. [Abstract] [Full Text] [PDF]
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H. Steiner, A. Capell, B. Pesold, M. Citron, P. M. Kloetzel, D. J. Selkoe, H. Romig, K. Mendla, and C. Haass Expression of Alzheimer's Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation J. Biol. Chem., November 27, 1998; 273(48): 32322 - 32331. [Abstract] [Full Text] [PDF]
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T. Tomita, S. Tokuhiro, T. Hashimoto, K. Aiba, T. C. Saido, K. Maruyama, and T. Iwatsubo Molecular Dissection of Domains in Mutant Presenilin 2 That Mediate Overproduction of Amyloidogenic Forms of Amyloid beta Peptides. INABILITY OF TRUNCATED FORMS OF PS2 WITH FAMILIAL ALZHEIMER'S DISEASE MUTATION TO INCREASE SECRETION OF Abeta 42 J. Biol. Chem., August 14, 1998; 273(33): 21153 - 21160. [Abstract] [Full Text] [PDF]
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G. Verdile, R. N. Martins, M. Duthie, E. Holmes, P. H. St George-Hyslop, and P. E. Fraser Inhibiting Amyloid Precursor Protein C-terminal Cleavage Promotes an Interaction with Presenilin 1 J. Biol. Chem., June 30, 2000; 275(27): 20794 - 20798. [Abstract] [Full Text] [PDF]
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G. Yu, F. Chen, M. Nishimura, H. Steiner, A. Tandon, T. Kawarai, S. Arawaka, A. Supala, Y.-Q. Song, E. Rogaeva, et al. Mutation of Conserved Aspartates Affects Maturation of Both Aspartate Mutant and Endogenous Presenilin 1 and Presenilin 2 Complexes J. Biol. Chem., August 25, 2000; 275(35): 27348 - 27353. [Abstract] [Full Text] [PDF]
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M. Okochi, S. Eimer, A. Bottcher, R. Baumeister, H. Romig, J. Walter, A. Capell, H. Steiner, and C. Haass A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Abeta 42 Generation in Human Cells J. Biol. Chem., December 22, 2000; 275(52): 40925 - 40932. [Abstract] [Full Text] [PDF]
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D. Seiffert, J. D. Bradley, C. M. Rominger, D. H. Rominger, F. Yang, J. E. Meredith Jr., Q. Wang, A. H. Roach, L. A. Thompson, S. M. Spitz, et al. Presenilin-1 and -2 Are Molecular Targets for gamma -Secretase Inhibitors J. Biol. Chem., October 27, 2000; 275(44): 34086 - 34091. [Abstract] [Full Text] [PDF]
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F. Chen, D.-S. Yang, S. Petanceska, A. Yang, A. Tandon, G. Yu, R. Rozmahel, J. Ghiso, M. Nishimura, D. M. Zhang, et al. Carboxyl-terminal Fragments of Alzheimer beta -Amyloid Precursor Protein Accumulate in Restricted and Unpredicted Intracellular Compartments in Presenilin 1-deficient Cells J. Biol. Chem., November 17, 2000; 275(47): 36794 - 36802. [Abstract] [Full Text] [PDF]
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H. Steiner, T. Revesz, M. Neumann, H. Romig, M. G. Grim, B. Pesold, H. A. Kretzschmar, J. Hardy, J. L. Holton, R. Baumeister, et al. A Pathogenic Presenilin-1 Deletion Causes Abberrant Abeta 42 Production in the Absence of Congophilic Amyloid Plaques J. Biol. Chem., March 2, 2001; 276(10): 7233 - 7239. [Abstract] [Full Text] [PDF]
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W. A. Maltese, S. Wilson, Y. Tan, S. Suomensaari, S. Sinha, R. Barbour, and L. McConlogue Retention of the Alzheimer's Amyloid Precursor Fragment C99 in the Endoplasmic Reticulum Prevents Formation of Amyloid beta -Peptide J. Biol. Chem., June 1, 2001; 276(23): 20267 - 20279. [Abstract] [Full Text] [PDF]
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H. Iwata, T. Tomita, K. Maruyama, and T. Iwatsubo Subcellular Compartment and Molecular Subdomain of beta -Amyloid Precursor Protein Relevant to the Abeta 42-promoting Effects of Alzheimer Mutant Presenilin 2 J. Biol. Chem., June 8, 2001; 276(24): 21678 - 21685. [Abstract] [Full Text] [PDF]
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T. Tomita, T. Watabiki, R. Takikawa, Y. Morohashi, N. Takasugi, R. Kopan, B. De Strooper, and T. Iwatsubo The First Proline of PALP Motif at the C Terminus of Presenilins Is Obligatory for Stabilization, Complex Formation, and gamma -Secretase Activities of Presenilins J. Biol. Chem., August 24, 2001; 276(35): 33273 - 33281. [Abstract] [Full Text] [PDF]
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F. Kirschenbaum, S.-C. Hsu, B. Cordell, and J. V. McCarthy Glycogen Synthase Kinase-3beta Regulates Presenilin 1 C-terminal Fragment Levels J. Biol. Chem., August 10, 2001; 276(33): 30701 - 30707. [Abstract] [Full Text] [PDF]
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C. A. Saura, T. Tomita, S. Soriano, M. Takahashi, J.-Y. Leem, T. Honda, E. H. Koo, T. Iwatsubo, and G. Thinakaran The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Abeta 42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants J. Biol. Chem., May 26, 2000; 275(22): 17136 - 17142. [Abstract] [Full Text] [PDF]
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E. Pack-Chung, M. B. Meyers, W. P. Pettingell, R. D. Moir, A. M. Brownawell, I. Cheng, R. E. Tanzi, and T.-W. Kim Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor J. Biol. Chem., May 5, 2000; 275(19): 14440 - 14445. [Abstract] [Full Text] [PDF]
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M. S. Wolfe and C. Haass The Role of Presenilins in gamma -Secretase Activity J. Biol. Chem., February 16, 2001; 276(8): 5413 - 5416. [Full Text] [PDF]
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W. P. Esler, W. T. Kimberly, B. L. Ostaszewski, W. Ye, T. S. Diehl, D. J. Selkoe, and M. S. Wolfe Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate PNAS, March 5, 2002; 99(5): 2720 - 2725. [Abstract] [Full Text] [PDF]
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L. Kulic, J. Walter, G. Multhaup, D. B. Teplow, R. Baumeister, H. Romig, A. Capell, H. Steiner, and C. Haass Separation of presenilin function in amyloid beta -peptide generation and endoproteolysis of Notch PNAS, May 23, 2000; 97(11): 5913 - 5918. [Abstract] [Full Text] [PDF]
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Y.-M. Li, M.-T. Lai, M. Xu, Q. Huang, J. DiMuzio-Mower, M. K. Sardana, X.-P. Shi, K.-C. Yin, J. A. Shafer, and S. J. Gardell From the Cover: Presenilin 1 is linked with gamma -secretase activity in the detergent solubilized state PNAS, May 23, 2000; 97(11): 6138 - 6143. [Abstract] [Full Text] [PDF]
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D. Levitan, J. Lee, L. Song, R. Manning, G. Wong, E. Parker, and L. Zhang PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling PNAS, October 9, 2001; 98(21): 12186 - 12190. [Abstract] [Full Text] [PDF]
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