Presenilins: A new gene familiy involved in Alzheimer´s disease pathology

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Presenilins: a new gene family involved in Alzheimer´s disease pathology

C. Van Broeckhoven, Laboratory of Neurogenetics, University of Antwerp

Molecular geneticists have used the positional cloning strategy to identify genes that are involved in Alzheimer's disease (AD), the most common neurodegenerative disorder of the central nervous system causing dementia. Knowledge of these genes and their gene products should help clarify many of the questions relating to the primary biochemical pathways leading to neurodegeneration and neuronal cell death in AD. To date, 4 genes are known that play a role in AD pathology: the amyloid precursor protein (APP) gene on chromosome 21, the apolipoprotein E (APOE) gene on chromosome 19, presenilin-1 (PS-1) gene on chromosome 14 and presenilin-2 (PS-2) on chromosome 1. The latter 2 genes: the PS genes, have been identified very recently and belong to a new family of genes coding for transmembrane proteins with a currently unknown function.

The PS-1 gene was identified first following a genome-wide search for AD genes in families with presenile AD (onset age < 60 years) . A region on chromosome 14 at 14q24.3 was identified to contain an AD gene. Cloning of the candidate region into yeast artificial chromosomes (YACs) allowed the identification of a previously unknown gene, presenilin-1 or PS-1, by a method named direct cDNA selection. Several missense mutations were found in the PS-1 gene in a large number of presenile AD families of different ethnic origin, suggesting that PS-1 is a major gene for familial presenile AD . However, in a large set of presenile AD families involvement of chromosome 14q24.3 and thus PS-1 was excluded .These families are known as the Volga-German families, a group of families that originated from Germany, moved to Russia and later to the USA. Therefore, it was predicted that in these Volga-German families presenile AD is the result of a common founder mutation . A genome-wide search using polymorphic genetic markers spread throughout the genome resulted in the identification of a candidate region on chromosome 1 at 1q31-42, a region of approximately 14 Mb . The candidate region was again cloned into YACs and gene cloning experiments aiming at identifying the responsible AD gene were initiated. While this work was in progress the PS-1 gene on chromosome 14 was identified, an important finding that directly lead to the identification of the chromosome 1 gene, presenilin-2 or PS-2. Computer search with the PS-1 gene sequence of a gene data bank, containing a collection of partial gene sequences obtained in human genome mapping projects, identified a sequence with very high similarity to PS-1. The corresponding gene, named presenilin-2 or PS-2, was isolated and shown to map on chromosome 1 within the candidate region identified in the Volga-German families . Subsequently, mutation analysis of PS-2 of Volga-German AD patients showed a missense mutation at codon 141 substituting an asparagine for an isoleucine (11e141 Asp). The same mutation was present in 7 out of 9 Volga-German AD families confirming that these families are descendants of a common ancestor. That mutations in PS-2 are not restrictet to this special group of Volga-German families was demonstrated by the finding of a second mutation in PS-2, Met239Val, in an Italian presenile AD family .

The PS proteins share an overall homology of 67%, they have roughly 450 amino acids and their amino acid sequence predicts an integral membrane protein with at least 7 transmembrane domains. PS-1 and PS-2 share the highest similarity in the putative transmembrane domains with less similarity found in the N-terminal domain and in the central region of the large hydrophilic loop between transmembrane domains VI and VII were PS-2 is 24 amino acid residues shorter 6,7. Mutations are scattered over the PS protein indicating that most parts of the protein are functionally important2. Also, a mutation in one PS gene inevitably leads to AD pathology. The high sequence homology between both PS proteins suggests that they may have a similar biological function.

Their putative seven transmembrane structure is compatible with a function as a receptor molecule, an ion channel or a membrane structural protein. No data is available yet that explains the role of PS proteins in normal and abnormal functioning in the brain, however, interesting homologies have been observed with the proteins SPE-4 and SEL-12 from the worm Caenorhabditis elegans suggesting a role for PS proteins in intracellular protein transport and/or cell-cell signalling2. It is clear that with the identification of the PS-2 gene by Levy-Lahad and coworkers a whole new family of interesting genes has emerged. Many investigators will now dedicate their work to the unravelling of both the normal and pathological function of the PS proteins by using techniques such as cDNA transfection in cultured cells or transgenic mice. Although, 1995 was an exciting year for those working in the field of AD molecular genetics. 1996 will probably be even more exciting because of the load of new data that will become available shedding light onto the complex pathology of AD.


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Prof. Dr. C. Van Broeckhoven Laboratory of Neurogenetics University of Antwerp (UIA) Universiteitsplein 1 B-2610 Antwerpen

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