Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters.
Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters.
复制标题
内体/溶酶体CLC氯化物转运蛋白功能障碍引起的神经变性。
DOI：
10.3389/fcell.2021.639231
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发表时间：
2021
影响因子：
5.5
通讯作者：
Stauber T
中科院分区：
文献类型：
--
作者：
Bose S;He H;Stauber T
管腔离子浓度的调节对于细胞内细胞器的功能和细胞间的运输至关重要。几十年来，酸性pH在内体-溶酶体途径的隔间中的重要性已经广为人知。除了将质子泵入细胞器管腔的V-ATPase外，多种离子转运体和通道也参与了细胞器复杂离子动态平衡的调节。其中包括CLC家族的胞内成员，CLC-3到CLC-7。它们定位于不同但重叠的内体-溶酶体途径的隔间，部分具有组织特异性表达。作为2Cl-−/H+交换体，它们能支持泡囊酸化并积累腔内的Cl-−。患者和小鼠模型中编码基因的突变是严重表型的基础，包括患有CLCN5的肾结石和患有CLCN7的骨化症或色素减退。在神经元中表达的细胞内CLC功能障碍会导致神经元缺陷。与ClC-4异构体的内体ClC-3的缺失会导致神经变性。ClC-4基因突变与癫痫脑病和智力残疾有关。缺乏晚期内体ClC-6的小鼠会患上一种降低疼痛敏感度的溶酶体储积病。人类基因变异与癫痫有关，而功能获得突变会导致早发性神经退化。溶酶体ClC-7的功能障碍会导致溶酶体储存疾病和人类的神经变性。一般说来，氯化鲁米诺减少和钙调节改变与溶酶体储存疾病有关。本文综述了神经退行性疾病中细胞内体和溶酶体的氯、−/H+交换的性质，以及细胞离子转运的各种变化如何影响细胞器离子的稳态和功能。
The regulation of luminal ion concentrations is critical for the function of, and transport between intracellular organelles. The importance of the acidic pH in the compartments of the endosomal-lysosomal pathway has been well-known for decades. Besides the V-ATPase, which pumps protons into their lumen, a variety of ion transporters and channels is involved in the regulation of the organelles' complex ion homeostasis. Amongst these are the intracellular members of the CLC family, ClC-3 through ClC-7. They localize to distinct but overlapping compartments of the endosomal-lysosomal pathway, partially with tissue-specific expression. Functioning as 2Cl−/H+ exchangers, they can support the vesicular acidification and accumulate luminal Cl−. Mutations in the encoding genes in patients and mouse models underlie severe phenotypes including kidney stones with CLCN5 and osteopetrosis or hypopigmentation with CLCN7. Dysfunction of those intracellular CLCs that are expressed in neurons lead to neuronal defects. Loss of endosomal ClC-3, which heteromerizes with ClC-4, results in neurodegeneration. Mutations in ClC-4 are associated with epileptic encephalopathy and intellectual disability. Mice lacking the late endosomal ClC-6 develop a lysosomal storage disease with reduced pain sensitivity. Human gene variants have been associated with epilepsy, and a gain-of-function mutation causes early-onset neurodegeneration. Dysfunction of the lysosomal ClC-7 leads to a lysosomal storage disease and neurodegeneration in mice and humans. Reduced luminal chloride, as well as altered calcium regulation, has been associated with lysosomal storage diseases in general. This review discusses the properties of endosomal and lysosomal Cl−/H+ exchange by CLCs and how various alterations of ion transport by CLCs impact organellar ion homeostasis and function in neurodegenerative disorders.
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影响因子：
13.6
作者：
Chen CC;Krogsaeter E;Butz ES;Li Y;Puertollano R;Wahl-Schott C;Biel M;Grimm C
通讯作者：
Grimm C
影响因子：
3.3
作者：
Cortez, M. A.;Li, C.;Bear, C. E.
通讯作者：
Bear, C. E.
影响因子：
6.2
作者：
Di Zanni，Eleonora;Palagano，Eleonora;Picollo，Alessandra
通讯作者：
Picollo，Alessandra
影响因子：
64.8
作者：
Duan, D;Winter, C;Horowitz, B
通讯作者：
Horowitz, B
影响因子：
6.2
作者：
Barvencik, Florian;Kurth, Ingo;Amling, Michael
通讯作者：
Amling, Michael