TY - JOUR
T1 - Presenilins and calcium signaling - Systems biology to the rescue
AU - Bezprozvanny, Ilya
PY - 2013/7/9
Y1 - 2013/7/9
N2 - Mutations in presenilins result in familial Alzheimer's disease (FAD). Presenilins encode a catalytic subunit of the γ-secretase complex, and FAD mutations in presenil-ins alter γ-secretase activity. Many FAD mutations in presenilins also affect intracel-lular calcium signaling. To explain these results, it was proposed that presenilins also function as endoplasmic reticulum (ER) calcium leak channels and that this function is disrupted by FAD mutations. Although this hypothesis has been controversial, new research supports the calcium leak channel hypothesis. One group reported the presence of putative ion-conduction pore in the high-resolution crystal structure of bacterial presenilin homolog PSH1. Another group identifi ed an essential role for presenilins in mediating ER calcium leak in a cell-based screen for calcium homeostasis modulators. These results should enable the fi eld to move forward and to focus on exploring connections between FAD mutations in presenilins, changes in γ-secretase and ER Ca2+ leak functions, and development of the disease.
AB - Mutations in presenilins result in familial Alzheimer's disease (FAD). Presenilins encode a catalytic subunit of the γ-secretase complex, and FAD mutations in presenil-ins alter γ-secretase activity. Many FAD mutations in presenilins also affect intracel-lular calcium signaling. To explain these results, it was proposed that presenilins also function as endoplasmic reticulum (ER) calcium leak channels and that this function is disrupted by FAD mutations. Although this hypothesis has been controversial, new research supports the calcium leak channel hypothesis. One group reported the presence of putative ion-conduction pore in the high-resolution crystal structure of bacterial presenilin homolog PSH1. Another group identifi ed an essential role for presenilins in mediating ER calcium leak in a cell-based screen for calcium homeostasis modulators. These results should enable the fi eld to move forward and to focus on exploring connections between FAD mutations in presenilins, changes in γ-secretase and ER Ca2+ leak functions, and development of the disease.
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U2 - 10.1126/scisignal.2004296
DO - 10.1126/scisignal.2004296
M3 - Review article
C2 - 23838181
AN - SCOPUS:84880858909
VL - 6
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 283
M1 - pe24
ER -