Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP-43Q331K transgenic mouse model of amyotrophic lateral sclerosis
Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP-43Q331K transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1096/fj.201700835r
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发表时间：
2018-05-01
期刊：
影响因子：
4.8
通讯作者：
Noakes, Peter G.
中科院分区：
文献类型：
--
作者：
Chand, Kirat K.;Lee, Kah Meng;Noakes, Peter G.
dna结合蛋白43 （TDP-43）通过控制RNA转录、剪接和转运参与基因调控。TDP-43是肌萎缩性侧索硬化症（ALS）中发现的泛素包涵体的主要蛋白质成分；然而，TDP-43在神经肌肉交界处（NMJ）的功能及其在ALS发病机制中的作用在很大程度上是未知的。在这里，我们发现TDP-43(Q)（331K）突变导致小鼠在3月龄时神经传递受损，随后在10月龄时观察到运动功能缺陷和运动神经元丢失。这些缺陷表现为运动神经末梢突触囊泡的有效融合和释放，表现为量子含量减少和量子释放概率降低。我们观察到与TDP-43（Q331K）突变相关的形态学改变，如异常的神经分布模式和突触囊泡相关蛋白的分布，这表明NMJ正在经历突触重塑。这些发现支持了一个越来越被接受的观点，即NMJ功能失调是ALS病理的一个关键早期事件。
Transactive response DNA-binding protein-43 (TDP-43) is involved in gene regulation via the control of RNA transcription, splicing, and transport. TDP-43 is a major protein component of ubiquinated inclusions that are found in amyotrophic lateral sclerosis (ALS); however, the function of TDP-43 at the neuromuscular junction (NMJ) and its role in ALS pathogenesis is largely unknown. Here, we show that TDP-43(Q)(331K) mutation in mice resulted in impaired neurotransmission by age 3 mo, preceding deficits in motor function and motor neuron loss, which were observed from age 10 mo. These defects were in the effective fusion and release of synaptic vesicles within the motor nerve terminal and manifested in decreased quantal content and reduced probability of quantal release. We observed morphologic alterations that were associated with the TDP-43(Q331K) mutation, such as aberrant innervation patterns and the distribution of synaptic vesicle-related proteins, which is indicative of a failing NMJ undergoing synaptic remodeling. These findings support a growing acceptance that dysregulation of the NMJ function is a key early event in the pathology of ALS.