ORAI2 in Human Neuroglioma Cells: History
Subjects: Cell Biology
Contributors:
Cristina Fasolato

Reduction of Store-Operated Calcium Entry (SOCE) is common to both familial and sporadic Alzheimer's Disease (AD). Targeting SOCE subunits might be a tool to rescue Ca2+ dysfunctions in AD. Strategies that recover Ca2+ defects should also favor Aβ removal and/or contrasting its accumulation.

  • Alzheimer’s Disease
  • amyloid-beta
  • neuroglioma cells
  • ORAI2
  • calcium entry
  • stores
  • Amyloid Precursor Protein
  • SOCE

1.

Figure1. In this study, authors focus on the human neuroglioma cell line H4 and its clone H4-APPswe that stably expresses the FAD-linked amyloid precursor protein (APP) Swedish mutation. These cells are a good model to modulate glial store-operated calcium entry (SOCE) components [1][2]and, at the same time, to verify how this modulation affects Aβ accumulation. Of note, glial cells, among the other relevant features also directly participate in Aβ production[3][4][5][6], especially upon increased cellular stress caused by different environmental factors [7] and neuroinflammation [8].

Alzheimer’s Disease (AD), in both its familial and sporadic forms, is characterized by the neuronal secretion and deposition of Aβ peptide, which leads to the formation of the amyloid plaques, eventually leading to neuronal death [9][10]. Aβ is the product of amyloid precursor protein (APP) proteolysis, performed by two enzymes, β and ϒ-secretases. The last proteolytic cleavage, leading to Aβ production, is performed by either presenilin-1 or 2 (PS1, PS2), whose mutations, together with those of APP, are linked to the familial form of AD [11]. Specifically the enzyme, comprising either PS1 or PS2, called ϒ-secretase, produces several proteolytic variants of the Aβ peptide, among which the Aβ40 and Aβ42 isoforms are the most common [10]. In AD mouse models, as well as in AD patients brains, the stoichiometric ratio between the two variants is altered, favouring the longer version, which is more prone to oligomerisation and deposition. 

Aβ accumulation has been linked to Ca2+ signaling, with store-operated calcium entry (SOCE) playing a primary role. However, up until now conflicting results have been reported. SOCE inhibition and activation were respectively linked to Aβ  augmentation and decrement. Of note, SOCE downregulation occurs in both familial and sporadic AD[12][13][14][15]. 

SOCE is comprised of an endoplasmic reticulum (ER) resident Ca2+ sensor (STIM1 or STIM2), and a plasma membrane channel-forming subunit (ORAI1, ORAI2, or ORAI3) [1][2]. Upon depletion of the store Ca2+ content, STIM proteins oligomerize, leading to the formation of punctae on the ER membrane, which in turn recruit the ORAI subunit on the plasma membrane. ORAIs are relatively small (25-30 kDa) proteins, characterized by four trans-membrane domains; when contacted by STIM they oligomerize into homo- and/or hetero-hexamers to form a channel with a high Ca2+ selectivity and very low unitary conductance [16][17].

In neuroglioma cells, authors have characterized the effect of increased and decreased ORAI2 expression on SOCE level and ER Ca2+ content and found that ORAI2 [18] downregulation significantly increases SOCE amplitude while leading to a marked reduction in the Aβ42/Aβ40 ratio in the extracellular environment. We suggest ORAI2 as a novel therapeutic target in AD because its downregulation allows for the rescue of SOCE reduction, while reducing Aβ42 secretion by glial cells.

References

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