Czeredys Magdalena
Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Front Cell Dev Biol. 2020 Dec 23;8:611735. doi: 10.3389/fcell.2020.611735. eCollection 2020.
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) signalosome. Recent research has shown that one of the major Ca signaling pathways, store-operated Ca entry (SOCE), is significantly elevated in HD. SOCE refers to Ca flow into cells in response to the depletion of endoplasmic reticulum Ca stores. The dysregulation of Ca 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 release-activated Ca current (I) and store-operated Ca current (I), 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.
亨廷顿舞蹈症（HD）是一种进行性神经退行性疾病，其特征为运动、认知和精神问题。它由亨廷顿蛋白中的多聚谷氨酰胺扩增引起，通过包括参与钙（Ca）信号体的基因在内的多个基因的转录失调导致纹状体变性。最近的研究表明，主要的钙信号通路之一，即储存-操作性钙内流（SOCE），在HD中显著升高。SOCE是指细胞内钙流入以响应内质网钙储存的耗尽。钙稳态失调被认为是HD进展的一个原因，因为在HD模型中，在疾病出现首个症状之前，SOCE通路在纹状体的γ-氨基丁酸（GABA）能中型多棘神经元（MSN）中被突变的亨廷顿蛋白（HTT）间接且异常地激活。本综述总结了最近的研究，这些研究揭示了HD病理学与不同HD模型中SOCE升高之间的关系，这些模型包括YAC128小鼠（一种HD转基因模型）、细胞HD模型以及从成年HD患者成纤维细胞获得的诱导多能干细胞（iPSC）来源的GABA能中型多棘神经元（MSN）。MSN中的SOCE被证明是由至少两个不同通道组的电流介导的，即钙释放激活钙电流（I）和储存-操作性钙电流（I），它们由基质相互作用分子（STIM）蛋白和Orai或瞬时受体电位通道（TRPC）通道组成。讨论了它们在HD生理和病理条件下的作用。还总结了亨廷顿相关蛋白1同工型A在HD MSN中SOCE升高方面的作用以及可能稳定HD中SOCE升高的潜在化合物。有证据表明，HD MSN神经元中SOCE分子成分或SOCE上游通路的失调是HD的一个标志，这些变化可能导致HD病理学，使其成为潜在的治疗靶点。
