By John Hardy, National Institute on Aging, Bethesda, MD

View Presenilin-1 Diagram (2006 version by K. Dillen and W. Annaert)
View Presenilin-1 Diagram (2002 version by R. Crook)
View Presenilin-2 Diagram
View Presenilin-1 Mutations Table
View Presenilin-2 Mutations Table

With the realization that the APP gene accounted for only a minority of cases of autosomal dominant Alzheimer's disease (see APP Mutation Directory), the race was on to find other gene(s) that might lead to this form of the disease. This was perceived as an important goal in its own right, but it was also felt that it might offer some independent test of the 'amyloid cascade hypothesis.' With the benefit of hindsight, there had been some evidence that chromosome 14 might be involved, as there was an-all-but-forgotten linkage report suggesting a locus towards the telomere of chromosome 14 (Weitkamp et al., 1983). The first proper report of genetic linkage, however, came from the Seattle group (Schellenberg et al., 1992) and was quickly followed by confirmatory reports from other major groups (St. George-Hyslop et al., 1992, Van Broeckhoven et al., 1992, Mullan et al., 1992). Clearly, the major locus for early onset, autosomal dominant Alzheimer's disease was on chromosome 14q. Significantly, the Volga German group of families did not show linkage to this locus, strongly suggesting that there was also a third locus.

Gradually, the region containing the locus was narrowed down (Cruts et al., 1995), and efforts intensified to try and clone the gene using classical positional cloning strategies (because none of the candidate genes known to be in the region had mutations). In a tour de force, Sherrington and colleagues identified presenilin 1 (1995). Unlike the case of APP, there were no previous data implicating the presenilins in Alzheimer's disease, and Sherrington and colleagues only knew it was the gene for one reason—the best possible: all their "linked" families had mutations. In the meantime, the Seattle group had identified a linkage to chromosome 1 in the Volga German families, but this finding was 'in press' when the cloning of presenilin 1 was published (Levy-Lahad et al., 1995a). As soon as each group learned of the structure of the presenilin 1 protein, they searched databases for homologies and realized that a very similar gene was located on chromosome 1. Sure enough, this second gene mapped into the Volga German region and mutations were quickly identified in this gene, presenilin 2 (Levy-Lahad et al., 1995b, Rogaev et al., 1995).

The two genes are highly homologous at the DNA sequence, protein sequence, and gene structure levels (Alzheimer's Collaborative Group, 1995). The proteins are believed to have either 6 or 8 transmembrane domains. A large number of mutations have now been found (see table, diagram, and http://molgen-www.uia.ac.be/ADMutations/). The function of the presenilins and their mode of dysfunction in Alzheimer's disease are largely outside the scope of this review. However, with regard to their function, a key observation has been that they are homologous to the C. elegans proteins sel-12 and spe-4 (Levitan and Greenwald, 1995, L'Hernault and Arduengo, 1992) and are involved in the Notch signalling pathway (Levitan et al., 1996, Baumeister et al., 1997). With regard to their dysfunction in Alzheimer's disease, the observation that they lead to altered APP processing in the same apparent way as APP717 mutations, in patients with mutations has proved to be of seminal importance (Scheuner et al., 1996) and replicable in both transfected cells (Citron et al., 1997, Mehta et al., 1997) and transgenic animals (Borchelt et al., 1996, Duff et al., 1996).

Most of the pathogenic mutations are missense mutations to residues which are conserved between the two proteins. They are not randomly distributed, but cluster in exon 8 and along faces of the transmembrane alpha-helices (Crook et al., 1997, Perez-Tur et al., 1996). There are, however, a few exceptions to rule this rule, as described below:

The Delta 9 mutation

The delta 9 mutation can be caused by mutations in the splice acceptor site of exon 9 (Perez-Tur et al., 1995: Sato et al., 1998) or by deletion of the whole genomic section of the gene (Prihar et al., 1999). The mutation results in the deletion of residues 291-319 of the protein and the change of S290C at the splice site. The deletion alters the metabolism of presenilin as it deletes the major cleavage site of presenilin 1 (Thinakaran et al., 1996: Podlisny et al., 1997). Despite this major effect on presenilin metabolism, recent data has suggested that the "pathogenic" mutation is S290C since simply changing this residue affects APP metabolism in the same way as the full mutation (Steiner at al., 1999).

The delta 9 mutation is the one most associated with an unusual pathological and clinical phenotype (Crook et al., 1998). In this phenotype, spastic paraparesis is the first symptom, followed several years later by a dementing process. The pathology of individuals with this mutation are not the conventional neuritic plaques of Alzheimer's disease, but rather large "cotton wool" plaques without neuritic reaction or a evidence of glial reactivity. Other mutations also sometimes lead to this phenotype (Kwok et al., 1997). The relation of the delta 9, and other presenilin mutations to the unusual pathology and the relation of both the mutation and the pathology to the clinical features remains unclear: it may be of significance that the delta 9 mutation has a particularly large effect on APP processing (Mehta et al., 1998, Citron et al., 1997).

The Delta 4 mutation

The delta 4 mutation is a splice donor site mutation (Tysoe et al. 1998). This mutation causes a large number of different transcripts many of which are truncated: however the pathogenic transcript is almost certainly the one with a simple insertion in at the splice site (T113-114ins). This transcript, like all the other missense mutations tested, increases A-beta-42 production in transfected cells (DeJonghe et al., 1999). This mutation illustrates well the fact that all the pathogenic mutations maintain the overall structure of the protein and all mutations affect APP processing (Murayama et al., 1999)

Are there any other pathogenic loci for early onset autosomal dominant Alzheimer's disease?

Epidemiological studies suggest that the APP and presenilin mutations together account for a fairly small proportion of cases of early onset disease, even amongst those designated as 'familial' (Cruts et al., 1998). However, we are not aware of the existence of any families that lack any of these known mutations and have multiply affected individuals over three generations with cousins affected by the same disease. This suggests, but does not prove, that the simple pathogenic loci have all been identified, and that other familial clustering is likely to be oligogenic rather than monogenic in etiology.

View Presenilin-1 Mutations Table
View Presenilin-1 Mutations Diagram

References

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