Calsenilin reverses presenilin-mediated enhancement of calcium signaling.
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.
Leissring
M A
MA
Laboratories of Molecular Neuropathogenesis, and Molecular and Cellular Neurobiology, Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4545, USA.
Yamasaki
T R
TR
Wasco
W
W
Buxbaum
J D
JD
Parker
I
I
LaFerla
F M
FM
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D053764:Presenilin-1; D053766:Presenilin-2; D012097:Repressor Proteins; D014982:Xenopus laevis
D002135:Calcium-Binding Proteins; D007295:Inositol Phosphates; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D012097:Repressor Proteins; C118500:inositol 3,4,5-trisphosphate