Modulation of Ca2+ refilling mediated by ORAI-1, STIM1 and NCX as a new therapeutical strategy in neurodegeneration

Physiological Ca2+ signals are essential for cell function and survival. On the other hand, perturbations of intracellular Ca2+ homeostasis can enhance mechanisms leading to cell death. In respect to the Ca2+-induced cytotoxicity in neuronal and non-neuronal cells of CNS, “source specificity hypothesis” reasons that it occurs not simply as a function of increased Ca2+ levels, but is instead linked to the route of Ca2+ entry (1). Accordingly, calcium-mediated degeneration, in general, may occur through different mechanisms implying the dysregulation of both specific plasma membrane and intracellular proteins as well as several Ca2+-dependent signaling pathways. In these conditions, some elements become unable to correctly transduce vital signals from the plasma membrane to the intracellular compartments. The identification of specific targets involved in this route may re-equilibrate cell status thus interfering with the neurodegenerative process and inducing a certain Ca2+ remodeling process. Moreover, impaired Ca2+ homeostasis is now considered an important feature of dysfunctional motor neurons in ALS. Accordingly, the stimulation of Akt/ERK1/2 signaling pathway via a rapid intracellular Ca2+ increase is able to prevent endoplasmic reticulum (ER) stress in Guam type of ALS (2). Interestingly, under these conditions, Ca2+ ions partially flow from the extracellular space and partially derive from ER (2), likely through the Ca2+ release induced by Ca2+-mobilizing second messengers (i.e. IP3 and/or the NAD+-derived second messengers cADPR or NAADP)(3). Moreover, a part the important role played by plasma membrane proteins in regulating Ca2+ homeostasis at neuronal level, also Ca2+-storing organelles play an important role in buffering intracellular calcium ions. When dysfunctional, Ca2+ stores may trigger death pathways. Among these organelle, nuclear envelope (NE) is now considered an emerging Ca2+-storing organelle whose dysfunction can enhance cell death process. In this view, it has been postulated that the leakiness of nuclear pore complex, mediated by calcium overload, may trigger neuronal demise through the alteration of nucleo-cytoplasmic transport thus determining cell condemned to death (4). In this symposium, the speakers will bring new elements to the discussion on “the source specificity hypothesis” related to the Ca2+-mediated degeneration in neurodegenerative disorders including ALS, Stroke, Alzheimer’s disease as well as in PNS diseases associated to demyelination. Interestingly, an interrelationship of metabolic syndromes and neurodegenerative diseases has been postulated. Also in this respect, they will discuss about some newly identified targets involved in Ca2+ homeostasis control at both plasma membrane and intracellular level within the complex neuronal architecture.