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

Magdalena Czeredys

doi:10.3389/fcell.2020.611735

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.

Highlights

Calcium (Ca2+) ions are important universal second messengers that regulate numerous cellular processes
Increases in STIM2 expression elevated synaptic neuronal store-operated Ca2+ entry (SOCE) (nSOCE), which likely was involved in synaptic loss in medium spiny neurons (MSNs) (Wu et al, 2016), whereas STIM1 expression was unchanged in Huntington’s disease (HD) MSNs
The RNA interference (RNAi)-mediated knockdown of channels that are involved in SOCE other than transient receptor potential channel 1 (TRPC1), such as TRPC6, Orai1, and Orai2, and knockout of the endoplasmic reticulum (ER) Ca2+ sensor STIM2 (Wu et al, 2016, 2018) resulted in the stabilization of spines and suppressed abnormal nSOCE in YAC128 MSNs. These results indicate that the molecular composition of the SOCE pathway in HD is complex and suggest the involvement of other players beyond STIM2 and TRPC1

Summary

Introduction

Calcium (Ca2+) ions are important universal second messengers that regulate numerous cellular processes. Increases in STIM2 expression elevated synaptic nSOCE, which likely was involved in synaptic loss in MSNs (Wu et al, 2016), whereas STIM1 expression was unchanged in HD MSNs. the CRISPRCas9-mediated knockdown of STIM2 caused the stabilization of dendritic spines in YAC128 MSNs. A key role for TRPC1 channels in supporting the SOC pathway was shown in an HD model.

Results

Conclusion