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

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

doi:10.1242/jcs.140939

Abstract

Mutations in either of two presenilin genes can cause familial Alzheimer's disease. Presenilins have both proteolysis-dependent functions, as components of the γ-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 γ-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.

Highlights

To date, more than 170 different mutations in presenilin 1 (PSEN1) and 13 mutations in presenilin 2 (PSEN2) genes are known to give rise to a familial form of Alzheimer’s disease (FAD) (De Strooper and Annaert, 2010)
More than half (67/112) of the residues in either PSEN1 or PSEN2 that are mutated in FAD are conserved in either Dictyostelium PsenA or PsenB [see fig
We have addressed the conservation of function of the Dictyostelium and human presenilins in development by analysing their ability to rescue the block mid-way through development observed in a psenA2/psenB2 mutant (Fig. 2)

Summary

Introduction

More than 170 different mutations in presenilin 1 (PSEN1) and 13 mutations in presenilin 2 (PSEN2) genes are known to give rise to a familial form of Alzheimer’s disease (FAD) (De Strooper and Annaert, 2010). The protein products of the mammalian PSEN genes are components of an aspartate protease complex, c-secretase (De Strooper, 2003), which is responsible for the regulated, intramembranous cleavage of a Received 23 August 2013; Accepted 29 December 2013 number of type 1 transmembrane proteins (Wolfe, 2006), including the Notch receptors (Huppert et al, 2000) and the amyloid precursor protein (APP). Understanding the discrete roles of presenilin proteins remains an important goal in understanding basic cell function and the progression of Alzheimer’s disease (De Strooper and Annaert, 2010)

Methods

Results

Conclusion