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

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          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 (Ca 2+) signalosome. Recent research has shown that one of the major Ca 2+ signaling pathways, store-operated Ca 2+ entry (SOCE), is significantly elevated in HD. SOCE refers to Ca 2+ flow into cells in response to the depletion of endoplasmic reticulum Ca 2+ stores. The dysregulation of Ca 2+ 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, Ca 2+ release-activated Ca 2+ current (I CRAC) and store-operated Ca 2+ current (I SOC), 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.

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          TRP channels.

          Kartik Venkatachalam, Craig Montell (2007)
          The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease.
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            A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.

            Stefan Feske, Yousang Gwack, Murali Prakriya … (2006)
            Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.
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              STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx.

              Jen Liou, Man Lyang Kim, Won Do Heo … (2005)
              Ca(2+) signaling in nonexcitable cells is typically initiated by receptor-triggered production of inositol-1,4,5-trisphosphate and the release of Ca(2+) from intracellular stores. An elusive signaling process senses the Ca(2+) store depletion and triggers the opening of plasma membrane Ca(2+) channels. The resulting sustained Ca(2+) signals are required for many physiological responses, such as T cell activation and differentiation. Here, we monitored receptor-triggered Ca(2+) signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca(2+)-store-depletion-mediated Ca(2+) influx, STIM1 and STIM2. These proteins have a single transmembrane region with a putative Ca(2+) binding domain in the lumen of the endoplasmic reticulum. Ca(2+) store depletion led to a rapid translocation of STIM1 into puncta that accumulated near the plasma membrane. Introducing a point mutation in the STIM1 Ca(2+) binding domain resulted in prelocalization of the protein in puncta, and this mutant failed to respond to store depletion. Our study suggests that STIM proteins function as Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx.
              Article 0 comments Cited 526 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Cell Dev Biol
                Journal ID (iso-abbrev): Front Cell Dev Biol
                Journal ID (publisher-id): Front. Cell Dev. Biol.
                Title: Frontiers in Cell and Developmental Biology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2296-634X
                Publication date (Electronic): 23 December 2020
                Publication date Collection: 2020
                Volume: 8
                Electronic Location Identifier: 611735
                Affiliations
                Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw , Warsaw, Poland
                Author notes

                Edited by: Agnese Secondo, University of Naples Federico II, Italy

                Reviewed by: Emanuele Giurisato, University of Siena, Italy; Rosely Oliveira Godinho, Federal University of São Paulo, Brazil

                *Correspondence: Magdalena Czeredys mczeredys@ 123456iimcb.gov.pl

                This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                DOI: 10.3389/fcell.2020.611735
                PMC ID: 7785827
                PubMed ID: 33425919
                SO-VID: 582289ea-6194-42b9-83e8-75fda668ef1b
                Copyright © Copyright © 2020 Czeredys.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 29 September 2020
                Date accepted : 01 December 2020
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 219, Pages: 21, Words: 17990
                Funding
                Funded by: Narodowe Centrum Nauki 10.13039/501100004281
                Award ID: no.2019/33/B/NZ3/02889
                Categories
                Subject: Cell and Developmental Biology
                Subject: Review

                Keywords: huntington disease,huntingtin,ca2+ signaling,neuronal store-operated ca2+ channels,neuronal store-operated ca2+ entry,medium spiny neurons,spines,huntingtin-associated protein 1 isoform a
                Data availability:
                Keywords: huntington disease, huntingtin, ca2+ signaling, neuronal store-operated ca2+ channels, neuronal store-operated ca2+ entry, medium spiny neurons, spines, huntingtin-associated protein 1 isoform a

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