An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum

作者：Ludtmann Marthe H R; Otto Grant P; Schilde Christina; Chen Zhi Hui; Allan Claire Y; Brace Selina; Beesley Philip W; Kimmel Alan R; Fisher Paul; Killick Richard; Williams Robin S B^*

来源：Journal of Cell Science, 2014, 127(7): 1576-1584.

DOI：10.1242/jcs.140939

• Dictyostelium
• gamma-secretase
• Presenilin

Mutations in either of two presenilin genes can cause familial Alzheimer%26apos;s disease. Presenilins have both proteolysis-dependent functions, as components of the gamma-secretase complex, and proteolysis-independent functions in signalling. In this study, we investigate a conserved function of human presenilins in the development of the simple model organism Dictyostelium discoideum. We show that the block in Dictyostelium development caused by the ablation of both Dictyostelium presenilins is rescued by the expression of human presenilin 1, restoring the terminal differentiation of multiple cell types. This developmental role is independent of proteolytic activity, because the mutation of both catalytic aspartates does not affect presenilin ability to rescue development, and the ablation of nicastrin, a gamma-secretase component that is crucial for proteolytic activity, does not block development. The role of presenilins during Dictyostelium development is therefore independent of their proteolytic activity. However, presenilin loss in Dictyostelium results in elevated cyclic AMP (cAMP) levels and enhanced stimulation-induced calcium release, suggesting that presenilins regulate these intracellular signalling pathways. Our data suggest that presenilin proteins perform an ancient non-proteolytic role in regulating intracellular signalling and development, and that Dictyostelium is a useful model for analysing human presenilin function.

• 出版日期2014-4-1
• 单位NIH