Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2000 Jul 18;97(15):8590-3.
doi: 10.1073/pnas.97.15.8590.

Calsenilin reverses presenilin-mediated enhancement of calcium signaling

M A Leissring  1 , T R Yamasaki, W Wasco, J D Buxbaum, I Parker, F M LaFerla
Affiliations

Calsenilin reverses presenilin-mediated enhancement of calcium signaling

M A Leissring et al. Proc Natl Acad Sci U S A. .

Abstract

Most cases of autosomal-dominant familial Alzheimer's disease are linked to mutations in the presenilin genes (PS1 and PS2). In addition to modulating beta-amyloid production, presenilin mutations also produce highly specific and selective alterations in intracellular calcium signaling. Although the molecular mechanisms underlying these changes are not known, one candidate molecular mediator is calsenilin, a recently identified calcium-binding protein that associates with the C terminus of both PS1 and PS2. In this study, we investigated the effects of calsenilin on calcium signaling in Xenopus oocytes expressing either wild-type or mutant PS1. In this system, mutant PS1 potentiated the amplitude of calcium signals evoked by inositol 1,4,5-trisphosphate and also accelerated their rates of decay. We report that calsenilin coexpression reverses both of these potentially pathogenic effects. Notably, expression of calsenilin alone had no discernable effects on calcium signaling, suggesting that calsenilin modulates these signals by a mechanism independent of simple calcium buffering. Our findings further suggest that the effects of presenilin mutations on calcium signaling are likely mediated through the C-terminal domain, a region that has also been implicated in the modulation of beta-amyloid production and cell death.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Immunoblot analysis of calsenilin (CLSN) and PS1 protein expression. Representative Western blot analysis of whole-cell protein extracts showing that CLSN and PS1 each accumulated to similar levels across experimental conditions. Similar results were obtained in oocytes harvested from each donor frog. Densitometric analysis of three independent immunoblots indicated that the levels of the different proteins differ by less than 5% across experimental conditions.
Figure 2
Figure 2
Calsenilin (CLSN) reverses the potentiation of calcium signaling conferred by wt and mutant PS1. Ins(1,4,5)P3-mediated calcium signaling in oocytes injected with water or CLSN alone (A), wt PS1 or wt PS1 plus CLSN (B), and PS1M146V or PS1M146V plus CLSN (C). (a) Representative families of calcium signals evoked by flash durations of 20, 45, and 90 ms in single oocytes. (b) Mean peak fluorescent intensity as a function of flash duration (n = 10–12 per condition). Note that the responses of control cells are shown for comparison (light solid lines) in Bb and Cb. (c) Mean responses after supramaximal Ins(1,4,5)P3 stimulation (n = 27–32 per condition; *, P < 0.001).
Figure 3
Figure 3
Calsenilin (CLSN) reverses the acceleration of decay rates conferred by mutant PS1. Quantitation of mean times to decay from peak ΔF/Fo to 1/2 peak (t1/2) for all calcium signals evoked by supramaximal Ins(1,4,5)P3 stimulation (n = 27–32 per condition). Note that decay rates are significantly accelerated by PS1M146V-expressing cells, whereas decay rates of wt PS1-expressing cells did not differ significantly from those of controls. *, P < 0.001 relative to controls and to cells coexpressing CLSN and PS1M146V.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Selkoe D J. Nature (London) 1999;399:A23–A31. - PubMed
    1. Leissring M A, Paul B A, Parker I, Cotman C W, LaFerla F M. J Neurochem. 1999;72:1061–1068. - PubMed
    1. Leissring M A, Parker I, LaFerla F M. J Biol Chem. 1999;274:32535–32538. - PubMed
    1. Guo Q, Furukawa K, Sopher B L, Pham D G, Xie J, Robinson N, Martin G M, Mattson M P. NeuroReport. 1996;8:379–383. - PubMed
    1. Guo Q, Fu W, Sopher B L, Miller M W, Ware C B, Martin G M, Mattson M P. Nat Med. 1999;5:101–106. - PubMed

Publication types

LinkOut - more resources