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Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
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UT Southwestern Medical Center at Dallas
This is an interesting paper that suggests a potential mechanism for reduction of store-operated calcium entry (SOC) in AD neurons. Our laboratory previously suggested that reduction in SOC calcium entry is one of the potential reasons for synaptic instability in AD neurons. In our study, we observed reduced levels of STIM2 in PS1-M146V KI neurons (Sun et al., 2014). The hypothesis in this paper by Tong at al. is that PS1-M146L and other PS1-FAD mutants are “gain of γ-secretase function” mutants that excessively cut STIM proteins, resulting in defective SOC. Similar to our findings, Tong at al. observed loss of mushroom spines in hippocampal neurons transfected with PS1-M146L mutant, which could be rescued by expression of STIM1 protein. Proposed mechanism may potentially be responsible for reduced levels of STIM proteins and SOC defects in PS1-FAD neurons. However, many PS1-FAD mutants reduce γ-secretase activity (Xia et al., 2015; Bentahir et al., 2006; Fernandez et al., 2014), and it remains to be determined how the proposed model works for these FAD mutants, as they would be expected to have reduced levels of STIM cleavage when compared to the wild type.
References:
Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ, Feske S, White CL 3rd, Bezprozvanny I. Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron. 2014 Apr 2;82(1):79-93. PubMed.
Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ 3rd. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015 Mar 4;85(5):967-81. PubMed.
Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
Fernandez MA, Klutkowski JA, Freret T, Wolfe MS. Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid β-peptides (Aβ) by γ-secretase to increase 42-to-40-residue Aβ. J Biol Chem. 2014 Nov 7;289(45):31043-52. Epub 2014 Sep 19 PubMed.
View all comments by Ilya BezprozvannyInternational Institute of Molecular and Cell Biology in Warsaw (IIMCB)
The paper brings an interesting mechanistic insight into the action of FAD PS1 on store-operated calcium entry (SOCE). It has long been known that FAD mutations in PS1 lead to a reduction in SOCE, whereas expression of catalytically-inactive PS1 mutants had a converse effect, thereby linking γ-secretase activity with SOCE. Although γ-secretase processes another FAD-linked protein, namely amyloid-precursor protein (APP), the involvement of APP in SOCE is controversial. Tong et al. now report that STIM1, a Ca2+ sensor in the ER, interacts with PS1 and is also processed by γ-secretase. The cleavage is increased in the presence of FAD PS1, leading to a smaller pool of STIM1 molecules that are capable of activating Orai1 plasma membrane calcium channels, explaining the observed effects on SOCE. Strikingly, the overall steady-state levels of STIM1 were hardly changed, which somewhat contrasts the findings of others showing more pronounced effects of PS1 on STIM1 or STIM2 levels (Bojarski et al., 2009; Sun et al., 2014). Despite these differences, a common paradigm appears to be that FAD PS1 attenuates SOCE by affecting STIM Ca2+ sensors, either through γ-secretase-dependent (this paper) or secretase–independent (Sun et al.) mechanisms. The common pathophysiological outcome is the reduced number of mushroom spines in FAD PS1 neurons (Tong et al., Sun et al.).
One can ask how relevant the data are for understanding the mechanisms of calcium disruption in Alzheimer’s disease. In my opinion the data may explain the pathology in familial cases of AD related to mutations in presenilins, but there is no clear mechanism to explain the effect of FAD APP mutations. We (Wegierski et al., 2016) and others found no effect of APP on SOCE. The most interesting outcome of the Tong et al. paper is that it indirectly strengthens the calcium hypothesis of sporadic AD proposed by Khachaturian (1994). The observation by Sun et al. that STIM2 is also decreased in the brains of SAD patients, together with our data showing dysregulation of calcium homeostasis, including SOCE, in fresh human lymphocytes isolated from people with SAD and MCI (Jaworska et al., 2013), indicate that targeting proteins of SOCE instead of Aβ might be an attractive alternative to anti-AD treatment. This is what we suggested in recent reviews (Wojda and Kuznicki, 2013; Majewski and Kuznicki, 2015).
References:
Bojarski L, Pomorski P, Szybinska A, Drab M, Skibinska-Kijek A, Gruszczynska-Biegala J, Kuznicki J. Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease. Biochim Biophys Acta. 2009 Jun;1793(6):1050-7. Epub 2008 Dec 6 PubMed.
Sun S, Zhang H, Liu J, Popugaeva E, Xu NJ, Feske S, White CL 3rd, Bezprozvanny I. Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron. 2014 Apr 2;82(1):79-93. PubMed.
Wegierski T, Gazda K, Kuznicki J. Microscopic analysis of Orai-mediated store-operated calcium entry in cells with experimentally altered levels of amyloid precursor protein. Biochem Biophys Res Commun. 2016 Sep 23;478(3):1087-92. Epub 2016 Aug 12 PubMed.
Khachaturian ZS. Calcium hypothesis of Alzheimer's disease and brain aging. Ann N Y Acad Sci. 1994 Dec 15;747:1-11. PubMed.
Jaworska A, Dzbek J, Styczynska M, Kuznicki J. Analysis of calcium homeostasis in fresh lymphocytes from patients with sporadic Alzheimer's disease or mild cognitive impairment. Biochim Biophys Acta. 2013 Jan 24; PubMed.
Wojda U, Kuznicki J. Alzheimer's disease modeling: ups, downs, and perspectives for human induced pluripotent stem cells. J Alzheimers Dis. 2013 Jan 1;34(3):563-88. PubMed.
Majewski L, Kuznicki J. SOCE in neurons: Signaling or just refilling?. Biochim Biophys Acta. 2015 Sep;1853(9):1940-52. Epub 2015 Jan 31 PubMed.
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