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Alzheimer’s disease (AD) is linked to mutations in a variety of genes. Four genetic loci are known to be associated with AD. AD1 results from mutations of the b-amyloid precursor protein gene located on Chromosome 21 (1). AD 2 is linked to the presence of the e4 allele of the APOE gene on Chromosome 19 (1). AD3 and AD4 are attributed to mutations in genes that encode the human presenilin transmembrane proteins, PS1 on Chromosome 14 and PS2 on Chromosome 1, respectively (2,3). Work exploring proteins that interact with the presenilins has identified a novel gene, Nicastrin, that is located on Chromosome 1 in a region showing linkage to AD (4). Several other genes are also implicated in sporadic AD and familial AD (FAD) including the Liproprotein Receptor-like Protein (LRP) gene and the gene that encodes a-2-macroglobulin (a2MG).
AD is characterized by the appearance of neurofibrillary tangles (NFT) and amyloid plaques in nervous tissue. The tangles are masses of proteins that include the microtubule-associated protein, Tau. NFTs form inside neural cells and interfere with cellular activities. Amyloid plaques are deposits of proteins, in particular the amyloidogenic form of b-amyloid protein (Ab1-42(43)). b-amyloid is a small protein fragment that is cleaved from a larger membrane protein, the Amyloid Precursor Protein (APP), presumably at the plasma membrane (5). Although clinicians can make a presumptive diagnosis of AD based on a specific progression of changes in memory and behavior as well as some biochemical tests, the only way currently to positively confirm AD is through post-mortem analysis (or biopsy examination) of the brain tissue for NFTs and amyloid plaques.
In 1995 scientists published the sequence of two related genes in which mutations were clearly linked to early-onset FAD (2,3). These two genes encoded novel transmembrane proteins of unknown function related to a previously described membrane protein from C. elegans (6). Since that announcement, more highly related homologs have been identified in C. elegans [SEL-12, (7); HOP-1, (8)], Drosophila (9), mice (2), rats (10), Xenopus (11) and Arabidopsis (GenBank accession number AC003981). These proteins are collectively called presenilins (PS-1, PS-2 in humans). The conservation of the presenilins in every multicellular organism investigated suggests that these proteins perform a fundamental biological role.
The presenilins are multiple-pass transmembrane domain proteins that localize to the enoplasmic reticulum and Golgi apparatus. Investigators also report localization to the nuclear envelope (12), nuclear matrix (13) and endocytic compartments (14). Plasma membrane localization is still debated; so far only two reports suggest plasma membrane localization of the presenilins while most studies report lack of plasma membrane staining (15,16). The exact membrane topology of these proteins remains to be determined, but the presenilins are processed into two fragments that reassociate in membranes (17), and full length presenilin is also described from cells (17). Between the two most C-terminal transmembrane domains, the presenilins have a large, cytoplasmic hydrophilic loop region. This region appears to be important for a variety of protein-protein interactions. The C-terminal portion of the presenilins contains a very highly conserved motif PALPX(S/P)XXX(G/A)XX(F/C)(Y/C)F that is found in every homolog examined, and changes in this region are linked to mutant phenotypes in C. elegans (18).
Presenilin genes are expressed ubiquitously in mice and humans. Researchers have detected presenilin mRNA in heart, brain, kidney, pancreas and other tissues through Northern analysis (2,19). In situ studies of mouse embryos show PS1 expression throughout the embryo (20). Studies in the mouse also demonstrate that the presenilins are absolutely required for embryonic development. PS1 knockout mice show significant defects in axial skeleton patterning and cerebral cavitation (21,22). Evidence that PS1-/- mice show defects in development that are not limited to the nervous system, the ubiquitous presenilin expression, and their highly conserved nature indicate that presenilins play a fundamental biological role in multicellular organisms. One suggestion for this role is that the presenilins are involved in intracellular trafficking. A second suggestion for the role of presenilins is that they are responsible for the intramembrane enzymatic processing of certain proteins, such as Notch or APP.
Introduction and The Presenilins, |