Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD.
Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD.
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DOI：
10.1016/j.brainres.2018.02.011
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发表时间：
2018-08-15
期刊：
影响因子：
2.9
通讯作者：
Sattler R
中科院分区：
文献类型：
--
作者：
Starr A;Sattler R
肌萎缩性侧索硬化症（ALS）的特征是上下运动神经元的进行性变性，由于肌肉的去神经支配而导致致命的瘫痪。由于遗传、病理和症状重叠，ALS现在被认为是一种谱系疾病，与额颞叶痴呆（FTD）并列，后者是65岁以下人群痴呆症的第二大常见原因。有趣的是，在这两种疾病中，都有大量的RNA结合蛋白（rbp）发生突变并被认为是致病的，或者其功能障碍有助于疾病的发病机制。ALS/FTD中最常见的共有基因突变是C9ORF72 （C9）内含子1内的六核苷酸重复扩增。已经提出了三种可能重叠的毒性机制导致疾病发病机制：由于C9ORF72 mRNA的单倍表达不足而导致的功能丧失，重复RNA聚集体或RNA焦点的功能获得，以及重复相关的非atg启动的重复RNA翻译（RAN）为毒性二肽重复（DPRs）。无论病因机制如何，疾病症状最终是由三个区域的神经传递失败引起的：大脑、脊髓和神经肌肉连接处。在这里，我们回顾了C9 ALS/ ftd相关的突触功能障碍和这三个关键区域的异常神经元兴奋性，重点关注患者、动物模型和体外模型中形态学和突触形成、兴奋性和兴奋毒性的变化。我们将这些缺陷与其他形式的ALS和FTD中所见的缺陷进行比较，以寻找共享通路，并讨论在ALS和FTD患者的治疗干预中突触功能障碍的潜在靶点。
Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping putative toxic mechanisms causing disease pathogenesis have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
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影响因子：
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通讯作者：
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DOI：
10.3988/jcn.2013.9.2.65
发表时间：
2013-04
期刊：
Journal of clinical neurology (Seoul, Korea)
影响因子：
--
作者：
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影响因子：
11.2
作者：
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