STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Abstract

Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development.

Molecular Components of Store-Operated Calcium Channels in the Regulation of Neural Stem Cell Physiology, Neurogenesis, and the Pathology of Huntington’s Disease

“…Additionally, the neuroprotective effect of SOCE inhibitor, EVP4593 was shown in the stabilization of high protein levels of both total HTT and STIM2 via regulation of their expression (Vigont et al, 2021). Interestingly, the severity of Ca 2+ influx via SOCE was independent of CAG repeat length between juvenile-and adultonset HD iPSCs-derived MSNs (Vigont et al, 2021). Additionally, a similar increase of voltage-gated calcium uptakes was observed in both juvenile-and adult-onset HD iPSCs-derived MSNs (Vigont et al, 2021).…”

“…A recent publication by Vigont et al (2021) indicates that Ca 2+ signaling is highly elevated in iPSC-based GABAergic MSNs cultures from juvenile-onset HD patient containing 76 repetitions of CAG in mHTT. Authors specifically demonstrated -TRPC1-mediated elevation of Ca 2+ entry plays a role in adult hippocampal neurogenesis.…”

“…Moreover, G418, which is a known selective antagonist of STIM2 (Parvez et al, 2008) decreased SOCE in these cells. Vigont et al (2021) concluded that elevated expression of STIM2 underlies the excessive Ca 2+ entry through nSOCs in juvenile-onset HD pathology. Additionally, the neuroprotective effect of SOCE inhibitor, EVP4593 was shown in the stabilization of high protein levels of both total HTT and STIM2 via regulation of their expression (Vigont et al, 2021).…”

“…Vigont et al (2021) concluded that elevated expression of STIM2 underlies the excessive Ca 2+ entry through nSOCs in juvenile-onset HD pathology. Additionally, the neuroprotective effect of SOCE inhibitor, EVP4593 was shown in the stabilization of high protein levels of both total HTT and STIM2 via regulation of their expression (Vigont et al, 2021). Interestingly, the severity of Ca 2+ influx via SOCE was independent of CAG repeat length between juvenile-and adultonset HD iPSCs-derived MSNs (Vigont et al, 2021).…”

Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions

“…The construction of HD cell models with gene editing techniques that can be used to validate the efficacy of therapeutic agents has been described in several articles (An et al, 2012(An et al, , 2014Xu et al, 2017;Dunbar et al, 2019;Ooi et al, 2019;Malankhanova et al, 2020a). Earlier studies have reported high calcium influx (Vigont et al, 2021) and ultrastructural synapse defects (Malankhanova et al, 2020b) in a HD cell model. Furthermore, the frequency of ultrastructural synapse defects is related to the number of CAG repeats (Morozova et al, 2018).…”