Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased Aβ42 secretion in mammalian cells but impaired Notch/lin-I2 signalling in C. elegans

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Abstract
The presenilin proteins are involved in the proteolytic processing of transmembrane proteins such as Notch/lin-12 and the β-amyloid precursor protein (βAPP). Mutation of a conserved cysteine (Cys60Ser) in the C. elegans presenilin sel-12 has a loss-of-function effect on Notch/lin-12 processing similar to that of null mutations in sel-12. In contrast, in mammalian cells, most missense mutations increase β-secretase cleavage of βAPP. We report here that mutation of this conserved cysteine (Cys92Ser) in human presenilin 1 confers a loss-of- function effect in C. elegans, but causes increased Aβ42 secretion in mammalian cells. These data suggest that the role of presenilins in Notch/lin-12 signalling and βAPP processing are either separately regulated activities or independent activities of the presenilins.