Helen Peterkin & Howard Baylis. Presenilins are transmembrane proteins implicated in familial Alzheimers disease. The primary function of presenilins is as a subunit of the ? secretase protein cleavage complex, which is implicated in many signalling pathways. Presenilins have recently been suggested to play a role in calcium signalling, possibly through interactions with IP3 and ryanodine receptors1. The mechanism by which presenilins interact with Ca2+ signalling is unclear and it is this that we aim to dissect. Three presenilin genes are present in C. elegans,
sel-12,
hop-1 and
spe-4.
sel-12 and
hop-1 show greatest homology and display a degree of functional redundancy3. We are using
sel-12 and
hop-1mutants to investigate the relationship between presenilin activity and calcium signalling.
sel-12 is reported to be expressed in all tissues except the intestine2 and we have shown, by GFP tagging, that
hop-1 is expressed in the nervous system, pharynx and vulva in worms carrying a mutation which upregulates
hop-1 expression. Alterations in signalling pathways can affect physiology and behaviour in C. elegans and these changes can be assayed. Both IP3 and ryanodine receptors function in the pharynx and we have shown
sel-12 mutant animals have reduced pharyngeal pumping on food. Both chemosensory and mechanosensory abilities appear to be impaired in
sel-12 mutant animals. In addition all
sel-12 mutants show a reduction in locomotion in a number of dispersion and thrashing assays.
sel-12(
ty11), a reported loss of function mutant, has reduced overall speed when measured on food and this defect can be rescued by expression of the full length
sel-12 protein. We have also crossed animals carrying the
sel-12(
ty11) mutation with animals carrying gain and loss of function mutations in
itr-1, the IP3 receptor gene in C. elegans, to identify any genetic interactions. 1. LaFerla FM. (2002) Nature. 3, 862-872 2. Levitan DJ, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald IS. (1996) Proceedings of the National Academy of Sciences USA. 931, 4940-14944. 3. Xiajun L & Greenwald I. (1997) Proc. Natl. Acad. Sci. USA. 94, 12204-12209