Bandara S, Malmersjö S, Meyer T.
Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA.
Sci Signal. 2013 Jul 9;6(283):ra56.
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The ongoing and unresolved debates regarding presenilin serving as an ER leak channel are a worthy dialogue and the hypothesis valid to pursue. However, I’m in agreement with Ilya Bezprozvanny’s statement in his Perspective (Bezprozvanny 2013) on this paper by Bandara et al., that this unresolved controversy has marginalized the larger issue surrounding the calcium-regulating functions of presenilins and the essential role of intracellular Ca2+ dysregulation in AD pathogenesis. These findings from the Meyer lab provide another critical layer of evidence that a basic function of presenilin (PS2 specifically) involves regulating endoplasmic reticulum (ER) Ca2+ signaling. This is internally consistent with the wealth of studies associating AD-linked PS mutations with profound ER Ca2+ mishandling. Data from Bandara et al., indicate there is an ion-conducting pore within the PS2 haloprotein structure that could potentially pass Ca2+ from the ER lumen to the cytosol. PS2 mutations associated with AD are largely within this pore region, and thus may interfere with ER Ca2+ homeostasis. Since the athors did not discuss PS1, which is the subtype most often studied in AD models, it remains unclear whether this also has a putative pore-forming region.
Some of the controversy generated in the Ca2+/PS/AD field could reflect distinct mechanisms for PS1 and PS2 in regulating ER Ca2+. In a nice, neat world, we could imagine that PS1 may be regulating the inositol-3-phosphate receptor (IP3R) and the ryanodine receptor (RyR) in a manner consistent with findings by Foskett and Stutzmann, i.e. sensitized channel properties (see ARF related news), and if mutant PS1 has impaired leak properties, this is masked by the large Ca2+ responses generated by the sensitized channels. PS2, on the other hand, would be less redundant and serve the Ca2+ leak role in the ER and maintain proper Ca2+ load in the lumen. Thus, mutant PS2 would underlie the ER store abnormalities. Alternatively, common underlying mechanisms driven by impairments in PS1 or PS2 may be involved, such as increased ER Ca2+ store load, which sensitizes IP3R and RyR channels. The obligatory statement about more studies being needed to be done still apply, but at the very least, this contribution by Bandara et al., along with the biological evidence generated by labs invested in this line of questioning leave a clearer direction about how to proceed to resolve these issues. Regardless of outcome, the overarching umbrella supporting a role of ER Ca2+ dyshomeostasis in AD is strengthened.
Presenilins and calcium signaling-systems biology to the rescue.
Sci Signal. 2013 Jul 9;6(283):pe24.
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