The presenilin genes

Mutations in presenilin-1 (PS-1) and presenilin-2 (PS-2), two very similar genes on chromosome 14 and chromosome 1 respectively, also cause early-onset autosomal dominant AD.(55) The function of these genes is not fully understood, but homology with genes in flies and worms suggests that the presenilins participate in NOTCH signalling—a complex signal-transduction cascade critical, amongst other things, in determining neuronal cell fate. Mutations in the presenilin genes, and hence their role in AD pathogenesis, may result in an interference with the normal functioning of the protein or may induce a gain in a novel pathogenic function. Whatever the mechanism, it is clear that mutations in the presenilins result in an increase in the production of b-amyloid. (49) Therefore the finding of mutations in these genes adds to, rather than detracting from, the amyloid cascade hypothesis although, as with any hypothesis, the complexity of an originally simple idea increases.

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