On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases
“However, the dysregulation of ER Ca2+ homeostasis is one of the mechanisms affecting the selective loss of DA neurons of the substantia nigra pars compacta(Stefani et al., 2012; Calì et al., 2014). Unlike other neurons, rhythmic activity of DA neurons depends on L-type Cav1.3 channels. Pharmacological inhibition of these currents by izradipine restores Ca2+−independent “juvenile” pacemaking activity and protects DA neurons in animal models of the disease (Chan et al., 2007). In normal conditions, the pacemaking activity of DA neurons is inhibited by the TRPC1-STIM1 complex. Accordingly, increased L-type Cav1.3 currents were observed upon Stim1 or TRPC1 silencing. Interestingly, the neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+)—that mimics PD—decreases the level of TRPC1 and its interaction with STIM1, thus increasing neuronal death both in vitro and in vivo (Bollimuntha et al., 2005; Selvaraj et al., 2012). Molecularly, the decrease of TRPC1 expression leads to an abnormal increase in Cav1.3 activity, thereby causing degeneration of DA neurons (Sun et al., 2017; Figure 2). Despite the abnormal increase in L-type activity, downregulation of TRPC1 also leads to the loss of SOCE, thus triggering ER stress and initiation of the unfolded protein response (UPR) in DA neurons (Selvaraj et al., 2012). Conversely, in PC12 cell lines, Stim1 knockdown significantly attenuated 6-hydroxydopamine (6-OHDA)- and MPP±induced toxicity through inhibition of SOCE-mediated Ca2±overload (Li et al., 2013, 2014); while, pharmacological inhibition of SOCE by SKF-96365 was protective against MPP+ cytotoxicity (Chen et al., 2013). The effect on SOCE was related to Orai1 and L-type Ca2+ channels, but not to TRPC1 (Li et al., 2014). Moreover, Stim1 knockdown attenuated 6-OHDA- and MMP±induced mitochondrial Ca2+ uptake and dysfunction in PC12 cells (Li et al., 2013, 2014). This further underscores that STIM1, through SOCE, may be responsible for neuronal oxidative stress induced by ER stress and mitochondrial dysfunction in PD.
In support of the important role of SOCE for DA neurons survival, the mutant dominant-negative form of Orai1 channel leads to tyrosine hydroxylase downregulation in Drosophila thus affecting dopamine synthesis and release (Pathak et al., 2015). Furthermore, skin fibroblasts from idiopathic PD patients and patients bearing familial R747W mutation in PLA2g6 gene, that encodes for a Ca2± independent phospholipase A2, exhibit depleted stores and reduced SOCE (Zhou et al., 2016). Overall, these findings indicate that SOCE pathway in DA neurons represents an attractive target for PD drug discovery (Pchitskaya et al., 2018).”
