Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.
Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.
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DOI：
10.1186/s40035-021-00278-7
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发表时间：
2022-01-25
影响因子：
12.6
通讯作者：
Chu CT
中科院分区：
文献类型：
--
作者：
Verma M;Lizama BN;Chu CT
谷氨酸是哺乳动物中枢神经系统中最常见的神经递质，起着介导兴奋性神经传递的作用。然而，高水平的谷氨酸能输入会引起兴奋性毒性，导致中风和创伤等急性脑损伤后的神经细胞死亡。虽然兴奋性毒性细胞死亡也与一些神经退行性疾病模型有关，但急性凋亡性细胞死亡在慢性神经退行性疾病中的作用仍然存在争议。N-甲基-D-天冬氨酸受体部分拮抗剂的保护作用证明了兴奋性突触失调是导致神经退行性变的重要因素。在这里，我们回顾了亚致死性兴奋性损伤与帕金森氏病、阿尔茨海默病、肌萎缩侧索硬化症和亨廷顿病相关的神经退行性变的证据。与经典的兴奋性毒性不同，新的证据表明兴奋性突触后神经变性中线粒体钙处理功能失调。我们讨论了调控线粒体钙摄取和释放的机制，LRRK2，PINK1，Parkin，β-淀粉样蛋白和葡萄糖脑苷酶对线粒体钙转运蛋白的影响，以及自噬线粒体丢失在轴突萎缩中的作用。最后，我们讨论了正常化钙流入和流出线粒体基质的策略，从而防止线粒体钙毒性和兴奋性毒性树突状细胞丢失。虽然线粒体钙摄取增加或释放减少的机制在不同的模型系统中有所不同，但一套常见的使线粒体钙通量正常化的策略可以防止兴奋性线粒体毒性，并可能在多种疾病背景下具有神经保护作用。
Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.
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DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
DOI：
10.1016/j.bbadis.2013.01.004
发表时间：
2013-04-01
影响因子：
6.2
作者：
Cali, Tito;Ottolini, Denis;Brini, Marisa
通讯作者：
Brini, Marisa
DOI：
10.1083/jcb.201002108
发表时间：
2010-08-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cherra SJ 3rd;Kulich SM;Uechi G;Balasubramani M;Mountzouris J;Day BW;Chu CT
通讯作者：
Chu CT
影响因子：
4.7
作者：
Budd, SL;Nicholls, DG
通讯作者：
Nicholls, DG
影响因子：
7.7
作者：
Bhujabal, Zambarlal;Birgisdottir, Asa B.;Johansen, Terje
通讯作者：
Johansen, Terje