Open Access

The presenilins

Genome Biology20023:reviews3014.1

https://doi.org/10.1186/gb-2002-3-11-reviews3014

Published: 23 October 2002

Summary

The presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical significance of this regulation is shown by the contribution of presenilin mutations to 20-50% of early-onset cases of inherited Alzheimer's disease. Although the precise molecular mechanism underlying presenilin function or dysfunction remains elusive, presenilins are thought to be part of a complex of proteins that has 'γ-secretase cleavage' activity, which is clearly central in the pathogenesis of Alzheimer's disease. Mutations in presenilins increase the production of the longer isoforms of amyloid β peptide, which are neurotoxic and prone to self-aggregation. Biochemical studies indicate that the presenilins do not act alone but operate within large heteromeric protein complexes, whose components and enzymatic core are the subject of much study and controversy; one essential component is nicastrin. The presenilin primary sequence is remarkably well conserved in eukaryotes, suggesting some functional conservation; indeed, defects caused by mutations in the nemotode presenilin homolog can be rescued by human presenilin.

Gene organization and evolution history

The presenilin 1 (PS1) gene on human chromosome 14 (14q24.3) was initially discovered by genetic analysis of a subset of pedigrees in which the Alzheimer's disease is transmitted as a pure autosomal dominant trait [1]. The closely related PS2 gene on chromosome 1 (1q42.2) was identified subsequently by sequence homology [2,3]. Both PS1 and PS2 genes are organized into ten translated exons that display tissue-specific alternative splicing [2,4,5,6,7]. The functions and biological importance of differentially spliced presenilin variants are poorly understood; differential expression of isoforms may lead to differential regulation of the proteolytic processing of the β-amyloid precursor protein (βAPP; see later). For example, aberrant PS2 transcripts lacking exon 5 increase the rate of production of amyloid β peptide (Aβ, the neurotoxic peptide implicated in Alzheimer's disease) [8], whereas naturally occurring isoforms without exons 3 and 4 and/or without exon 8 do not affect production of Aβ [6,9].

GenBank database searches using the full length PS1 sequence suggest that presenilin-like proteins are phylogenetically ancient and well-conserved across diverse eukaryote species, including plants, molluscs, insects, fish, birds, and mammals [10,11,12,13,14,15,16]. Functional conservation of presenilins in most non-human species is undetermined, except in the nematode Caenorhabditis elegans, in which a deficiency in Sel-12, the PS1 homolog, induces an egg-laying defect that can be rescued by expression of human PS1 [17,18]. Additional presenilin homologs were recently identified in disparate eukaryotes by their homology to the PS1 transmembrane domains, suggesting that the presenilin family may be more common than previously contemplated [19,20].

Characteristic structural features

Mammalian PS1 and PS2 are synthesized as 50 kDa polypeptides, each predicted to traverse the membrane 6-10 times; the ammo and carboxyl termini are both oriented towards the cytoplasm [21]. The current model, with eight transmembrane domains, is shown in Figure 1. More than 100 different missense mutations and two splicing-defect mutations in the PS1 gene have been reported (Table 1) [22,23]. These are dispersed throughout the PS1 sequence, with the majority of mutations clustered near membrane interfaces in the highly conserved transmembrane domains or in hydrophobic residues in either the amino-terminal domain or the putative loop domain between transmembrane domains 6 and 7.
Figure 1

A molecular model of Presenilin-1. The protein is thought to have eight transmembrane domains. Residues associated with mutations found in familial Alzheimer's disease are colored as indicated in the key. 'Endoproteolysis' indicates the approximate site of the imprecise cleavage of the molecule.

Table 1

Mutations in the presenilin genes

PS1

Codon

Location

Mutation

Phenotype

35

Amino-terminal domain

Arg→Gln

FAD

79

Amino-terminal domain

Ala→Val

FAD, onset 64 years

82

TM1

Val→Leu

FAD, onset 55 years

94

TM1

Val→Met

See [71]

96

TM1

Val→Phe

FAD, onset 53 years

105

TM1/TM2 loop

Phe→Leu

FAD, onset 52 years

113-114 (insert)

TM1/TM2 loop

Insert Thr

FAD, onset 35 years

115

TM1/TM2 loop

Tyr→His

FAD, onset 37 years

115

TM1/TM2 loop

Tyr→Cys

FAD, onset 42 years

116

TM1/TM2 loop

Thr→Asn

FAD, onset 37 years

117

TM1/TM2 loop

Pro_Leu

AD, onset 28 years

120

TM1/TM2 loop

Glu_Asp

FAD, onset 48 years

120

TM1/TM2 loop

Glu_Lys

FAD, onset 37 years

123

TM1/TM2 loop

Glu_Lys

FAD, onset 56-62 years

135

TM2

Asn_Asp

FAD, onset 36 years

139

TM2

Met_Thr

FAD, onset 49 years

139

TM2

Met_Val

FAD, onset 40 years

139

TM2

Met_Ile

AD

139

TM2

Met_Lys

FAD, onset 37 years

143

TM2

Ile_Thr

FAD, onset 35 years

143

TM2

Ile_Phe

FAD, onset 55 years

146

TM2

Met_Leu

FAD, onset 45 years

146

TM2

Met_Val

FAD, onset 38 years

146

TM2

Met_Ile

FAD, onset 40 years

147

TM2

Thr_Ile

FAD, onset 42 years

156 + insert

TM3 interface

Tyr_ (Phe,Ile,Tyr)

FAD

163

TM3 interface

His_Arg

FAD, onset 50 years

163

TM3 interface

His_Tyr

FAD, onset 47 years

165

TM3

Trp_Cys

FAD, onset 42 years

169

TM3

Ser_Leu

FAD, onset 31 years

169

TM3

Ser_Pro

FAD, onset 35 years

171

TM3

Leu_Pro

FAD, onset 40 years

173

TM3

Leu_Trp

FAD, onset 27 years

177

TM3

Phe_Ser

FAD

178

TM3

Ser_Pro

FAD

184

TM3

Glu_Asp

FAD

206

TM4

Gly_Ser

FAD

209

TM4

Gly_Val

FAD, onset 30-48 years

209

TM4

Gly_Arg

FAD, onset 49 years

213

TM4 interface

Ile_Thr

FAD, onset 42-48 years

213

TM4 interface

Ile_Leu

FAD

219

TM4 interface

Leu_Pro

FAD

219

TM4 interface

Leu_Phe

See [71]

222

TM5

Gln_Arg

FAD

231

TM5

Ala_Thr

FAD, onset 52 years

231

TM5

Ala_Val

FAD

233

TM5

Met_Thr

FAD, onset 35 years

233

TM5

Met_Leu

FAD, onset 46 years

235

TM5

Leu_Pro

FAD, onset 32 years

237

TM5

Phe_Ile

AD with spastic paraparesis, 31 years

246

TM6

Ala_Glu

FAD, onset 55 years

250

TM6

Leu_Ser

FAD, onset 53 years

260

TM6

Ala_Val

FAD, onset 40 years

261

TM6

Val_Phe

FAD

262

TM6

Leu_Phe

FAD, onset 50 years

263

TM6/TM7 loop

Cys_Arg

FAD, onset 47 years

264

TM6/TM7 loop

Pro_Leu

FAD, onset 45 years

267

TM6/TM7 loop

Pro_Ser

FAD, onset 35 years

269

TM6/TM7 loop

Arg_Gly

FAD, onset 47 years

269

TM6/TM7 loop

Arg_His

FAD, onset 47 years

273

TM6/TM7 loop

Glu_Ala

FAD, onset 63 years

274

TM6/TM7 loop

Thr_Arg

FAD

278

TM6/TM7 loop

Arg_Thr

FAD, onset 37 years

280

TM6/TM7 loop

Glu_Ala

FAD, onset 47 years

280

TM6/TM7 loop

Glu_Gly

FAD, onset 42 years

282

TM6/TM7 loop

Leu_Arg

FAD, onset 43 years

285

TM6/TM7 loop

Ala_Val

FAD, onset 50 years

286

TM6/TM7 loop

Leu_Val

FAD, onset 50 years

290

TM6/TM7 loop

Ser>Cys

FAD, onset 39-50 years

291-319 deletion

TM6/TM7 loop

Shortened loop

FAD

352 (insert)

TM6/TM7 loop

Insert Arg

FAD

354

TM6/TM7 loop

Thr_Ile

FAD

358

TM6/TM7 loop

Arg_Gln

FAD

365

TM6/TM7 loop

Ser_Tyr

FAD

378

TM7

Gly_Glu

FAD, onset 35 years

384

TM7

Gly_Ala

FAD, onset 35 years

390

TM7

Ser_Ile

FAD, onset 39 years

392

TM7

Leu_Val

FAD, onset 25-40 years

394

TM7

Gly_Val

FAD

405

TM7/TM8 loop

Asn_Ser

FAD, onset 48 years

409

TM8

Ala_Thr

FAD, onset 58 years

410

TM8

Cys_Tyr

FAD, onset 48 years

418

TM8

Leu_Phe

FAD

424

TM8

Leu_Arg

FAD, onset 33 years

426

TM8

Ala_Pro

FAD, onset 48-60 years

431

Carboxy-terminal domain

Ala_Glu

FAD

434

Carboxy-terminal domain

Ala_Cys

FAD

435

Carboxy-terminal domain

Leu_Phe

FAD

436

Carboxy-terminal domain

Pro_Ser

FAD, onset 48-60 years

436

Carboxy-terminal domain

Pro_Gln

FAD, onset 48-60 years

439

Carboxy-terminal domain

Ile_Val

FAD

PS2

Codon

Location

Mutation

Phenotype

62

N-term

Arg_His

AD, onset 62 years

122

TM1/TM2 loop

Thr_Pro

FAD, onset 46 years

141

TM2

Asn_Ile

FAD, onset 50-65 years

148

TM2

Val_Ile

AD, Onset 71 years

239

TM5

Met_Val

FAD, onset variable 45-

84 yrs

   

239

TM5

Met_Ile

FAD, onset 58 years

Compiled from [2,70,71]. Abbreviations: AD, Alzheimer's disease; FAD,familial Alzheimer's disease; TM, transmembrane segment; TM1/TM2 loop, the loop between transmembrane segments 1 and 2. The age of onset of disease is given if it is known.

Following synthesis, the PS1 and PS2 holoproteins undergo tightly regulated, but imprecise, endoproteolysis in their third cytoplasmic loop domain to generate an approximately 35 kDa amino-terminal fragment and an 18-20 kDa carboxy-terminal fragment, which remain associated with each other [24]. It is clear that cleavage of presenilins following export from the endoplasmic reticulum is governed by additional rate-limiting factors, such as nicastrin (see below), because overexpressed presenilins readily saturate the processing machinery and accumulate as holoproteins [25]. An additional proteolytic pathway is known to involve members of the caspase 3 family of proteases and may be involved in apoptosis [26].

Localization and function

Human PS1 and PS2 have distinct patterns of expression in human tissues. Whereas PS1 is transcribed uniformly throughout the brain and in peripheral tissues, the PS2 transcript is expressed at relatively low levels in the brain, except in the corpus collosum, where it is high; it is highly expressed in some peripheral tissues, such as pancreas, heart, and skeletal muscle [27]. The low PS2 levels in brain and the compensatory activity provided by PS1 may explain why PS2 mutations are infrequent and incompletely penetrant compared with PS1 mutations, which are fully penetrant [28,29].

The βAPP protein is cleaved by three different activities, called α-, β- and γ-secretases, to generate Aβ and other fragments. Members of the Notch family, which are involved in developmental signaling in many animals, undergo cleavage at a site (S3) within the transmembrane domain to release an intracellular domain (NICD). It is well established that presenilins are required for the γ-secretase cleavage of βAPP and for the S3 cleavage of Notch-family receptors [30]. For βAPP processing, γ-secretase cleavage is the final step of two distinct proteolytic pathways involving either an α-secretase - which precludes Aβ peptide formation - or a β-secretase, which releases the Aβ peptide, comprising the 40 or 42 carboxy-terminal residues of βAPP. It is uncertain whether the γ-secretase cleavage event occurs at the plasma membrane or during trafficking of βAPP. The usual downstream effect of presenilin mutations in individuals with presenilin-linked familial Alzheimer's disease is the accumulation of Aβ in the brain [31,32] and a shift in the site of the γ-secretase cleavage of βAPP to produce the longer Aβ peptide, spanning residues 1-42 (Aβ42). These main features can be recapitulated in cell culture or in animal models expressing mutant forms of PS1 [33,34,35]. Conversely, PS1-deficient mice are impaired in γ-secretase activity, have reduced Aβ secretion, and accumulate γ-secretase substrates (the carboxy-terminal βAPP fragments derived from α- and β-secretase processing; see Figure 2) [36].
Figure 2

The role of presenilins in the γ-secretase cleavage of Notch and βAPP. Notch is cleaved by tumor necrosis factor α converting enzyme (TACE), and its ligand binds to the part of Notch that remains attached to the membrane. βAPP is cleaved by either the γ-secretase pathway or the γ-secretase pathway to give a membrane-bound carboxy-terminal fragment (APP-CTF). Subsequent γ-secretase cleavage (in the transmembrane domain) of Notch or APP-CTF produces carboxy-terminal intracellular domains, NICD and AICD, respectively, which enter the nucleus and are thought to regulate gene expression. The γ-secretase cleavage of βAPP also produces the neurotoxic Aβ peptide, but only if βAPP has been first cleaved by γ-secretase (not γ-secretase). The γ-secretase complex includes, in addition to PS1, the presenilin-binding protein nicastrin; members of the Armadillo protein family, such as β-catenin, have also been detected in presenilin complexes, although their role is not understood. Aph-1 and Pen-2 may also participate in the γ-secretase complex.

Mutation of two highly conserved aspartate residues in the transmembrane domains of PS1 (Asp257 and Asp385, shown in blue in Figure 1) inactivates γ-secretase activity and reduces Aβ secretion [37]. The sequence motif around Asp385 is somewhat similar to a sequence within prepilins, a family of bacterial peptidases [38]; this has promoted speculation that presenilins are themselves aspartyl proteases responsible for γ-secretase activity and that the critical Asp257 and Asp385 residues form that catalytic center of the γ-secretase. Additional support for the idea that presenilins are the proteases that have γ-secretase activity comes from studies in which photoactivated inhibitors of γ-secretase activity were found to bind to PS1 and PS2 [39,40].

It should be noted that forms of PS1 with the D257A or D385A mutations integrate poorly into the heteromeric complexes that are considered necessary for γ-secretase function, raising the possibility that these transmembrane-domain mutations disable PS1 structurally [41]. Moreover, several lines of evidence show that the regulation of βAPP and Notch cleavage differs, however, and such evidence is difficult to reconcile with a direct enzymatic role for PS1 in γ-secretase cleavage. First, a naturally occurring splice variant of PS1 lacking the region (encoded by exon 8) that contains the critical Asp257 allows Aβ production but not cleavage of Notch [42]. Second, different presenilin mutations differentially affect Aβ production and Notch cleavage [43,44,45]. Third, some recently discovered γ-secretase inhibitors preferentially affect processing βAPP over that of Notch [46]. Together, these findings suggest the presenilins regulate proteolysis indirectly, perhaps by an effect on trafficking of βAPP or Notch or by activation of the γ-secretase.

The biological purpose of presenilin-dependent γ-secretase cleavage of βAPP is still unknown. By analogy with the signaling pathway downstream of cleaved Notch and NICD, recent studies have raised the intriguing possibility that the short-lived carboxyl-terminal stub of βAPP, called (βAPP intracellular domain (AICD), is released into the cytoplasm following γ-secretase cleavage and translocates to the nucleus (Figure 2), where it may regulate expression of components involved in mobilizing intracellular calcium stores [47,48,49]. Another proposal implicates βAPP as a regulator of the axonal transport of a subset of vesicles ferrying cargo to nerve terminals. This view is derived from the observations that βAPP interacts directly with the light chain of the transport protein kinesin [50], that the transport of a vesicular compartment containing PS1 and γ-secretase depends on βAPP [51], and that deletion of the Drosophila βAPP-like gene (dAPPL) or overexpression of either dAPPL or human (βAPP in Drosophila disrupts axonal transport [52,53]. In this scheme, γ-secretase cleavage of the βAPP by presenilin-containing complexes releases the carboxy-terminal portion of (βAPP that connects the transport vesicle to the transport machinery through interaction with kinesin, thereby disengaging the vesicle from microtubules upon arrival at its destination. Thus, presenilins may influence diverse cellular processes, such as intracellular signaling and axonal traffic.

In vitro studies of detergent-solubilized membranes show that γ-secretase activity resides within large multisubunit complexes that also contain presenilins. If presenilin molecules are excluded from these complexes, they are rapidly targeted for proteosome-mediated degradation [54]. On density gradients, presenilin holoproteins and the amino-and carboxy-terminal fragments of presenilins co-elute with high-molecular-weight markers (180 kDa for the holoproteins and 250-1000 kDa for the fragments [25,55]), presumably because they are part of larger complexes, and antibodies to PS1 coimmunoprecipitate heteromeric protein complexes that contain γ-secretase activity [56]. Conversely, affinity isolation with γ-secretase inhibitors co-purifies protein complexes containing PS1 [39,40]. Members of the Armadillo protein family (β- and δ-catenin, neural plakophilin-related armadillo protein (NPRAP), and p0071) [55,57,58] interact with presenilins but are not required for γ-secretase activity in vitro [40]. Other interactions whose role in γ-secretase activity is unknown have been reviewed previously [22].

More recently, PS1 and PS2 were found to interact with nicastrin, a novel single-pass transmembrane protein that is essential for processing of βAPP and Notch [59,60,61]. Nicastrin is clearly an important regulator of γ-secretase activity: nicastrin antibodies immunoprecipitate both presenilin and the active γ-secretase complex [40], and missense or deletion mutations within a conserved lumenal domain of nicastrin up- or down-regulate Aβ production in a manner that corresponds with PS1 binding, suggesting that γ-secretase activity is generated only after an obligatory interaction between nicastrin and PS1 [59]. Notch cleavage is affected similarly by nicastrin mutations, albeit to a lesser extent [60]. Moreover, nicastrin is essential for the normal processing of both βAPP and Notch homologs in Drosophila and C. elegans, and human nicastrin can partially rescue mutants of the C. elegans nicastrin homolog Aph-2 [59,61,62,63,64], suggesting that nicastrin function and its interactions with presenilins are conserved widely in non-mammalian species. Only mature glycosylated nicastrin that has passed through the Golgi compartment interacts with PS1 and is included in γ-secretase complexes [65]; overexpressed nicastrin fails to mature normally and accumulates within the endoplasmic reticulum. Moreover, entry of each of nicastrin and PS1 into γ-secretase complexes appears to be regulated by the other protein: the loss of one partner destabilizes the other [61,63,66,67].

Two potential new members of the PS-nicastrin complexes are homologs of Aph-1 and Pen-2, components of the C. elegans Glp-1/Notch signaling cascade that interact genetically with Sel-12/presenilin and Aph-2/nicastrin [68,69]. Primary sequence analysis suggests that Aph-1 and Pen-2 have seven and two membrane spanning domains, respectively, that are conserved in their respective Drosophila and human homologs. Human Aph-1 and Pen-2 can rescue C. elegans mutants lacking their homologs only when both transgenes are present together, implying that they act in concert. Moreover, reduction of Aph-1 and Pen-2 expression in Drosophila cells by RNA inhibition reduces γ-secretase activity [69]. Reduced expression of nematode Aph-1 causes mislocalization of Aph-2/nicastrin [68], and both Aph-1 and Pen-2 are required to maintain presenilin levels [69], suggesting that they regulate, or are components of, the presenilin-nicastrin γ-secretase complexes.

Frontiers

The identification of the additional γ-secretase components within the presenilin complexes is clearly an important task that lies ahead. The complexes purified to date are quite large, partly because of membrane impurities that remain associated following treatment with gentle detergents and partly because of interacting proteins that are not related to γ-secretase activity but are necessary for trafficking and maturation of the complex. The genetic cause of at least half of all cases of early onset familial Alzheimer's disease remain unexplained, and some of the unknown genes may have products that may modulate presenilin activity within γ-secretase complexes.

Declarations

Acknowledgements

We gratefully acknowledge grants from the Alzheimer Society of Ontario, the Canadian Institutes of Health Research, Scottish Rite Charitable Foundation, Ontario Mental Health Foundation, and the Alzheimer Society of Canada.

Authors’ Affiliations

(1)
Centre for Research in Neurodegenerative Diseases, University of Toronto, Queen's Park Crescent West
(2)
Department of Medicine, University of Toronto, Queen's Park Crescent West
(3)
Department of Medical Biophysics, University of Toronto, Queen's Park Crescent West

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