Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric problems. It is caused by a polyglutamine expansion in the huntingtin protein that leads to striatal degeneration via the transcriptional dysregulation of several genes, including genes that are involved in the calcium (Ca2+) signalosome. Recent research has shown that one of the major Ca2+ signaling pathways, store-operated Ca2+ entry (SOCE), is significantly elevated in HD. SOCE refers to Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The dysregulation of Ca2+ homeostasis is postulated to be a cause of HD progression because the SOCE pathway is indirectly and abnormally activated by mutant huntingtin (HTT) in γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) from the striatum in HD models before the first symptoms of the disease appear. The present review summarizes recent studies that revealed a relationship between HD pathology and elevations of SOCE in different models of HD, including YAC128 mice (a transgenic model of HD), cellular HD models, and induced pluripotent stem cell (iPSC)-based GABAergic medium spiny neurons (MSNs) that are obtained from adult HD patient fibroblasts. SOCE in MSNs was shown to be mediated by currents through at least two different channel groups, Ca2+ release-activated Ca2+ current (ICRAC) and store-operated Ca2+ current (ISOC), which are composed of stromal interaction molecule (STIM) proteins and Orai or transient receptor potential channel (TRPC) channels. Their role under physiological and pathological conditions in HD are discussed. The role of Huntingtin-associated protein 1 isoform A in elevations of SOCE in HD MSNs and potential compounds that may stabilize elevations of SOCE in HD are also summarized. Evidence is presented that shows that the dysregulation of molecular components of SOCE or pathways upstream of SOCE in HD MSN neurons is a hallmark of HD, and these changes could lead to HD pathology, making them potential therapeutic targets.

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

“…Although a few compounds have been shown to stabilize elevations of SOCE in HD models, future studies are necessary to evaluate their potential for HD therapy (Czeredys, 2020). No treatments for HD are currently available, but this disease may be a good candidate for cell replacement therapy because it is characterized by the relatively focal loss of MSNs that is caused by a mutation of HTT (Rosser and Bachoud-Lévi, 2012).…”

“…No treatments for HD are currently available, but this disease may be a good candidate for cell replacement therapy because it is characterized by the relatively focal loss of MSNs that is caused by a mutation of HTT (Rosser and Bachoud-Lévi, 2012). It was suggested that mHTT disrupts Ca 2+ signaling in MSNs and those changes could be a cause of HD progression (Raymond, 2017;Pchitskaya et al, 2018;Czeredys, 2020). Therefore transplantation of MSN progenitors without a mutation of HTT appears to be beneficial for HD patients.…”

“…The knockdown of molecular components of SOCE, including the Ca 2+ sensor STIM2 and Ca 2+ channels TRPC1, TRPC6, Orai1, and Orai2, resulted in the stabilization of dendritic spines and restored elevations of nSOCE in YAC128 MSNs (Wu et al, 2016;Wu J. et al, 2018). Although a few compounds have been shown to stabilize elevations of SOCE, such as tetrahydrocarbazoles (Czeredys et al, 2017(Czeredys et al, , 2018 and the quinizone derivative EVP4593 (an NF-κB antagonist which restores synaptic nSOCE and rescues abnormal spines in YAC128 MSNs in vitro and in vivo) (Wu et al, 2011(Wu et al, , 2016, future research is needed to determine whether they can serve as drug candidates for HD therapy (Czeredys, 2020). No effective treatments are currently available for HD.…”

Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases

“…At variance with AD, SOCE is elevated in HD [172][173][174][175]. In both in vitro and in vivo models, SOCE pathway is indirectly and abnormally activated by mutant HTT (mHTT) in striatal γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) before symptoms onset, thus highlighting the role of this Ca 2+ current in disease progression [101,176]. In fact, synaptic loss in MSNs was ascribed to SOCE elevation due to increased expression of STIM2, while STIM1 did not appear to be involved [174].…”

“…Indeed, NMDAR activation triggers Ca 2+ release from ER stores, STIM1 aggregation and SOCE stimulation in diverse experimental contexts [95,179]. Although there is evidence that compounds that stabilize abnormal SOCE may prevent dendritic spine loss in HD, further work is needed to clarify whether therapeutic strategies specifically acting on SOCE components, including STIMs, deserve further scrutiny to reverse Ca 2+ signalling dysregulation in HD [176].…”