NMJ-Analyser: high-throughput morphological screening of neuromuscular junctions identifies subtle changes in mouse neuromuscular disease models
NMJ-Analyser: high-throughput morphological screening of neuromuscular junctions identifies subtle changes in mouse neuromuscular disease models
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NMJ-Analyser：神经肌肉接头的高通量形态学筛选可识别小鼠神经肌肉疾病模型中的细微变化
DOI：
10.1101/2020.09.24.293886
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Maza A
中科院分区：
文献类型：
--
作者：
Maza A
神经肌肉连接（NMJ）是运动神经元轴突末端和肌纤维之间形成的外周突触。在许多神经肌肉疾病中，NMJs被认为是周围病理的主要部位，但在研究中，神经支配/去神经支配状态的定性评估往往缺乏系统的标准，并且与3D形态结构分开。在这里，我们描述了“nmj分析器”的发展，以全面筛选nmj的形态和相应的神经支配状态自动。NMJ- analyser生成29个生物学相关特征，定量定义健康和异常的神经肌肉突触，并应用机器学习来诊断NMJ变性。我们在野生型小鼠的纵向分析中验证了这一框架，以及四种不同的神经肌肉疾病模型：三种用于肌萎缩侧索硬化症（ALS），一种用于周围神经病变。我们发现NMJ的结构变化最初发生在突变型TDP43和FUS ALS模型的神经末梢。使用机器学习算法，健康和异常的神经肌肉突触的识别准确率为95%，灵敏度为88%，特异性为97%。我们的研究结果验证了NMJ-Analyser作为系统和结构筛选nmj的强大平台，并为神经肌肉疾病的可转移、交叉比较和高通量研究铺平了道路。
The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of ‘NMJ-Analyser’, to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases.
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