A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases A beta 42 generation in human cells

The familial Alzheimer's disease-associated presenilins (PSs) occur as a di meric complex of proteolytically generated fragments, which functionally su pports endoproteolysis of Notch and the beta -amyloid precursor protein (be ta APP). A homologous gene, sel-12, has been identified in Caenorhabditis e legans, We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteol ytic cleavage in C. elegans similar to the PSs in human tissue. In contrast , SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither S EL-12 wt nor C60S undergo endoproteolytic processing upon expression in hum an cells, suggesting that SEL-12 is cleaved by a C, elegans-specific endopr oteolytic activity. The loss of function of sel-12 in C. elegans is not ass ociated with a dominant negative activity in human cells, because SEL-12 C6 0S and the corresponding PS1 C92S mutation do not interfere with Notch1 cle avage. Moreover, both mutant variants increase the aberrant production of t he highly amyloidogenic 42-amino acid version of amyloid beta -peptide simi lar to familial Alzheimer's disease-associated human PS mutants. Our data t herefore demonstrate that the C60S mutation in SEL-12 is associated with ab errant endoproteolysis and a loss of function in C, elegans, whereas a gain of misfunction is observed upon expression in human cells.