Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease.
Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease.
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DOI：
10.3389/fcell.2020.611735
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发表时间：
2020
影响因子：
5.5
通讯作者：
Czeredys M
中科院分区：
文献类型：
--
作者：
Czeredys M
亨廷顿病（HD）是一种进行性神经退行性疾病，其特征在于运动、认知和精神问题。它是由亨廷顿蛋白中的多聚谷氨酰胺扩增引起的，其通过几个基因的转录失调导致纹状体变性，包括参与钙（Ca 2+）信号体的基因。最近的研究表明，主要的Ca 2+信号通路之一，钙库操纵的Ca 2+内流（SOCE），在HD中显著升高。SOCE是指响应于内质网Ca 2+储存的耗尽而流入细胞的Ca 2+。Ca 2+稳态失调被认为是HD进展的原因，因为在疾病的第一个症状出现之前，HD模型中来自纹状体的γ-氨基丁酸（GABA）能中型多刺神经元（MSN）中的突变亨廷顿蛋白（HTT）间接和异常激活了SOCE通路。本综述总结了最近的研究，揭示了HD病理学和不同HD模型中SOCE升高之间的关系，包括YAC 128小鼠（HD的转基因模型），细胞HD模型，和诱导多能干细胞（iPSC）为基础的GABA能中棘神经元（MSN），从成人HD患者成纤维细胞获得。研究表明，MSNs中的SOCE是由至少两种不同通道组的电流介导的，即Ca 2+释放激活的Ca 2+电流（ICRAC）和钙池操纵的Ca 2+电流（ISOC），它们由基质相互作用分子（STIM）蛋白和奥赖组成或瞬时受体电位通道（TRPC）通道。他们在HD的生理和病理条件下的作用进行了讨论。亨廷顿相关蛋白1亚型A在HD MSN中SOCE升高中的作用以及可能稳定HD中SOCE升高的潜在化合物也进行了总结。有证据表明，在HD MSN神经元中SOCE或SOCE上游通路的分子组分的失调是HD的标志，并且这些变化可能导致HD病理，使其成为潜在的治疗靶点。
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.
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影响因子：
64.5
作者：
BRILLANTES, AMB;ONDRIAS, K;MARKS, AR
通讯作者：
MARKS, AR
影响因子：
4
作者：
Berridge, MJ
通讯作者：
Berridge, MJ
影响因子：
3.5
作者：
Choo, YS;Johnson, GVW;Lesort, M
通讯作者：
Lesort, M
影响因子：
4.8
作者：
Cai, Xiangyu;Zhou, Yandong;Gill, Donald L.
通讯作者：
Gill, Donald L.
影响因子：
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作者：
Jung KO;Youn H;Lee CH;Kang KW;Chung JK
通讯作者：
Chung JK