On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases

Abstract

In both excitable and non-excitable cells, calcium (Ca2+) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca2+ refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca2+ signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca2+ homeostasis or mediate Ca2+ overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson’s disease (PD) models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer’s disease (AD) pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington’s disease (HD) transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up-regulation of SOCE may be beneficial during AD. These intriguing findings highlight the importance of further mechanistic studies to dissect the molecular pathways, and their corresponding targets, involved in synaptic dysfunction and neuronal loss during aging and neurodegenerative diseases.

“ER-Ca2+ sensor STIM regulates neuropeptides required for development under nutrient restriction in Drosophila”

“…Finally, there is growing evidence that SOCE is dysregulated in neurodegenerative diseases (59). In neurons derived from mouse models of familial Alzheimer's' disease (60) and early onset Parkinson's (51), reduced SOCE has been reported.…”

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

“…Sci. 2020, 21, 842 2 of 15 STIMs are essential players in maintaining neuronal Ca 2+ homeostasis (reviewed in [5][6][7]). The SOCE-related function of STIMs in neurons has previously been shown by [8,9].…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…Aβ aggregates and presenilin mutations have also been shown to alter the function of the ER Ca 2+ release channels, both ryanodine receptors (RyR), and inositol 1,4,5-trisphosphate receptors (IP 3 R), increasinh their sensitivity or expression level, and thus enhancing their Ca 2+ release activity [27,29,[38][39][40][41][42][43][44]. In contrast, the store-operated Ca 2+ entry pathway is downregulated in Alzheimer's disease models, although it is interesting to note that it has been shown to be upregulated in Huntington's disease models [27,29,32,45,46]. 4.…”