Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia; Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, NSW, 2522, Australia.
Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia; Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, NSW, 2522, Australia.
Neurosci Lett. 2019 Jun 21;704:89-94. doi: 10.1016/j.neulet.2019.04.001. Epub 2019 Apr 3.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease with familial forms linked to numerous mutations in a range of genes. The resulting variant proteins, including SOD1, TDP-43, and FUS, disturb protein homeostasis in a variety of ways and lead to the formation of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. These inclusions are made up of scores of proteins that do not appear at first to share obvious characteristics other than coaggregation. Recent evidence, however, suggests that these aggregating proteins can be characterized as being supersaturated in spinal motor neurons, as they exhibit cellular concentrations exceeding their solubilities. Here, we show that the average supersaturation of the entire spinal motor neuron proteome is greater than that of the ALS-resistant oculomotor neurons, suggesting that the vulnerability of spinal motor neurons is linked to the overall metastability of their proteome against aggregation. Consistently, ALS expression data suggest that affected neurons respond to pathology by transcriptional downregulation of supersaturated proteins, including specifically ion channels. These results identify a mechanism by which protein homeostasis imbalance leads to inclusion body formation in ALS, and to a disruption of other processes dependent on proteins that are supersaturated, thereby resulting in the dysfunctional excitability alterations observed in vivo.
肌萎缩侧索硬化症（ALS）是一种异质性运动神经元疾病，家族形式与多种基因的许多突变有关。由此产生的变异蛋白，包括 SOD1、TDP-43 和 FUS，以多种方式扰乱蛋白质的内稳态，并导致细胞内包含体的形成，这是疾病不同神经病理学亚型的特征。这些包含体由数十种蛋白质组成，乍一看似乎除了聚集之外没有明显的共同特征。然而，最近的证据表明，这些聚集的蛋白质可以被描述为在脊髓运动神经元中处于过饱和状态，因为它们表现出的细胞浓度超过了它们的溶解度。在这里，我们表明整个脊髓运动神经元蛋白质组的平均过饱和度大于 ALS 抵抗的眼动神经元，这表明脊髓运动神经元的脆弱性与其蛋白质组对聚集的整体亚稳性有关。一致地，ALS 表达数据表明，受影响的神经元通过转录下调过饱和蛋白（包括特定的离子通道）来对病理做出反应。这些结果确定了一种机制，即蛋白质内稳态失衡导致 ALS 中包含体的形成，并破坏了依赖于过饱和蛋白的其他过程，从而导致体内观察到的功能失调的兴奋性改变。
