An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease.
An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease.
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DOI：
10.3389/fncel.2014.00172
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发表时间：
2014
影响因子：
5.3
通讯作者：
Rao R
中科院分区：
文献类型：
--
作者：
Kondapalli KC;Prasad H;Rao R
自闭症是儿童发展的主要障碍，给社会带来巨大的情感和经济负担。近年来，迅速积累的遗传学证据表明，eNHE与多种神经系统疾病有关，包括自闭症、注意缺陷多动障碍(ADHD)、智能障碍和癫痫。eNHE是一种定位于细胞内小泡的Na+/H+交换器的子集。通过为V-ATPase泵浦的质子提供泄漏途径，eNHE确定管腔pH并调节早期和再循环内体隔室中的阳离子(Na+，K+)含量。由于泵和渗漏途径的不平衡，eNHE功能丧失突变会导致内膜腔酸化。NHE6和NHE9两种亚型在大脑中高表达，包括海马区和大脑皮层。在这里，我们总结了鲁米那阳离子含量和pH值对货物加工、交付和命运的重要性的证据。借鉴模式生物和哺乳动物细胞的见解，我们展示了eNHE如何影响膜受体和神经递质转运体的表面表达和功能。这些研究导致了突触前和突触后神经元和星形胶质细胞中eNHE活性的细胞模型，在这些模型中，它们可能会影响突触的发育和可塑性。对eNHE的研究为自闭症和其他衰弱的神经疾病的机制提供了新的见解，并为治疗干预开辟了新的可能性。
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na+/H+ exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na+, K+) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.
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影响因子：
4
作者：
Christianson, AL;Stevenson, RE;Schwartz, CE
通讯作者：
Schwartz, CE
影响因子：
11
作者：
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DOI：
10.1073/pnas.0706192104
发表时间：
2007-08-21
影响因子：
11.1
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影响因子：
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