Discrepancies in Two Recent Papers on ER Ca2+-leak Channels in Presenilin1, -2 Double Knockout Cells
This paper describes presenilin (PS)-related mechanisms that affect Ca2+ leak from the endoplasmic reticulum (ER). However, it points to a very different mechanism—Ca2+-channel leak properties of presenilin—to that which we have recently published: upregulation of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) (Kasri et al., 2006). Although these two conclusions are not mutually exclusive, the niggling point is that both papers report very different and even sometimes opposing experimental findings. There is no obvious explanation for these discrepancies, but it is clear that all methodologies currently applied to evaluate ER Ca2+ concentrations and ER Ca2+ leak are imperfect and often lead to contradictory results. This was extensively discussed by Clark Distelhorst and Gordon Shore in their recent review of the conflicting findings...  Read more

View all comments by Humbert De Smedt

The planar lipid bilayer approach was, therefore, an ideal preparation to start addressing presenilin function in membranes and its relation to the Ca2+ signaling dysregulation seen with certain AD-linked presenilin mutations. This technique allows one to insert specific channels of interest into a...  Read more

View all comments by Grace (Beth) Stutzmann

The first finding obtained by Bezprozvanny and colleagues, showing that PSs are leak channels, does not contradict our published data: we have repeatedly demonstrated that overexpression of wt-PS2 and, to a lesser extent, also of wt-PS1, reduces the ER Ca2+ level in different cell models (Zatti et al., 2004; Giacomello et al., 2005;...  Read more

View all comments by Giuliano Binetti
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View all comments by Sandro Sorbi

I performed aluminum neurotoxicity experiments on hippocampal rat neurons several years ago and found dantrolene and dimethylsulfoxide reduced cell death from aluminum toxicity, indicating aluminum toxicity may be mediated through release of calcium from intracellular stores and oxidative stress (1).

There may be multiple mechanisms disrupting calcium metabolism in the endoplasmic reticulum, including metals such as aluminum and other metals potentially capable of oxidation such as copper and iron. Oxidative...  Read more

View all comments by Steven Brenner

Under resting conditions, steady-state [Ca2+]L is determined by the dynamic equilibrium of two components: an active Ca2+ uptake mediated by ATP-dependent Ca2+ pumps of the SERCA family and passive Ca2+ efflux via leak channels. Even though this pump-leak cycle appears to be a common property of Ca2+-storing organelles, little is known about the proteins controlling the Ca2+ leak pathway. Several...  Read more

View all comments by Natalia Prevarskaya

Binetti and colleagues raise interesting questions about the effects of presenilin FAD mutations on ER Ca2+ content and on inositol trisphosphate receptor (InsP3R)-mediated Ca2+ release. We attempted to reconcile our results with that of Zatti at al.; however, we ran into significant difficulties in interpreting their data.

Let us consider an example of two PS1 FAD mutants for which extensive datasets are available from several laboratories. Zatti et al. reported that expression of PS1-M146L resulted in reduced Ca2+ response to cyclopiazonic acid (CPA) + histamine (Fig. 1C), no change in response to CPA + bradykinin (BK) (Fig. 1B), ...  Read more

View all comments by Ilya Bezprozvanny

In my opinion, the research by Bezprozvanny and colleagues emphasizes the importance of the fundamental role of free calcium modifications in cells undergoing biochemical changes underlying AD. While not questioning the key role of Aβ peptides in this disease, the data add another possible dimension to the key role performed by calcium in cellular stress and death following the biochemical modifications characterizing AD. Hence, some presenilin mutations affecting γ-secretase activity can impair cell viability by increasing Aβ peptide production or by shifting the latter towards the more amyloidogenic Aβ42, resulting in Aβ oligomerization and cell membrane(s) permeabilization. Other mutations that do...  Read more

View all comments by Massimo Stefani

Based on my critical analysis of the research data in comparison with AD features, I deduced a hypothesis for the mechanism of sporadic AD in 1998 [1]. This hypothesis, together with the report of the PS molecular structure [2], allowed me to predict that “presenilins most likely act as calcium channels in vivo and that their gene mutations may cause the disease by diminishing the Ca2+ channeling function” [3]. I also predicted that “Functional reconstitution and electrophysiological studies should directly reveal whether or not presenilins in artificial membranes could act as Ca2+ channels, and if so, whether the mutations would diminish the channeling function.” [2] It is thus encouraging to see, 8 years later, the elegant work by Tu et al. [3] showing that PS function as “calcium leak channels.” It has also shown that some FAD-linked mutations reduce the channel’s function [3].

The comments made by various...  Read more

View all comments by Ming Chen

Ghribi O, Herman MM, Pramoonjago P, Spaulding NK, Savory J. GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. Neurobiol Dis. 2004;16(2):417-27. Abstract

Ghribi O, Herman MM, Savory J. Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003;71(6):853-62. Abstract

View all comments by Othman Ghribi

Calcium dysregulations have long been considered as a part of neuronal toxicity in AD, as also shown by mutations in presenilins. Likewise, infected cells in prion disease show calcium elevation but the mechanisms causing cell death have remained elusive. This paper shows a possible mechanism by which disturbed calcium regulation causes cell death through a crosstalk between the ER and mitochondria leading ultimately to caspase activation. The paper is highly recommended.

View all comments by Dan Lindholm

The experimental design is very elegant and leaves no doubt that...  Read more

View all comments by Ilya Bezprozvanny

The challenge will be now to determine what are the signaling pathways—downstream from γ-secretase—involved in neuronal death in the aging brain. Cadherins may represent attractive candidates. Indeed, the cadherin family of cell-cell adhesion proteins is abundantly expressed at mature synapses, is critical for synaptic plasticity, and is cleaved by γ-secretase in neurons upon NMDA receptor stimulation (Marambaud et al., 2003). It is, therefore, reasonable to think that a loss of synaptic cadherin cleavage by γ-secretase may lead over time to defects in synaptic plasticity and neuronal integrity and thus may contribute to the phenotype observed in...  Read more

View all comments by Philippe Marambaud

In contrast with their previous paper in Neuron, Shen and colleagues now conclude that the neurodegeneration they see in both PS1 and 2 double KO mice, and nicastrin single KO mice is due to a γ-secretase defect, i.e., the loss of proteolytic function. This is part of an ongoing debate as to what extent postulated functions of presenilin outside the γ-secretase complex contribute to the overall phenotype of presenilin deficient mice. While I tend to believe that the neurodegeneration observed in their studies is indeed reflecting a real γ-secretase defect, the current paper is not conclusive in that regard. Indeed, knockout of nicastrin also destabilizes presenilin, and could theoretically affect functions of presenilin independent of its proteolytic function. However, I agree with Shen and colleagues that their current interpretation is the most likely one,...  Read more

View all comments by Bart De Strooper