Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Neurosci Lett. 2022 May 1;778:136614. doi: 10.1016/j.neulet.2022.136614. Epub 2022 Mar 31.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterised by the loss of motor neurons and subsequent paralysis. Evidence indicates that synaptic alterations are associated with the early stages of ALS pathogenesis. A hallmark of ALS postmortem tissue is the presence of proteinaceous inclusions, indicative of disturbed protein homeostasis, particularly in spinal cord motor neurons. We recently demonstrated that spinal cord motor neurons contain a supersaturated proteome, as they possess proteins at concentrations that exceed their solubility limits, resulting in a metastable proteome conducive to protein misfolding and aggregation. Recent evidence indicates metastable sub-proteomes within neuronal compartments, such as the synapse, may be particularly vulnerable and underlie their involvement in the initial stages of neurodegenerative diseases. To investigate if the motor neuron presynaptic terminal possesses a metastable sub-proteome, we used human and mouse spinal cord motor neuron expression data to calculate supersaturation scores. Here, we found that both the human and mouse presynaptic terminal sub-proteomes have higher supersaturation scores than the entire motor neuron proteome. In addition, we observed that proteins down-regulated in ALS were over-represented in the synapse. These results provide support for the notion that the metastability of the sub-proteome within the motor neuron presynaptic terminal may be particularly susceptible to protein homeostasis disturbances in ALS, and may contribute to explaining the observed synaptic dysfunction in ALS.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是运动神经元的丧失和随后的瘫痪。有证据表明，突触改变与 ALS 发病机制的早期阶段有关。ALS 死后组织的一个标志是存在蛋白质包含物，表明蛋白质稳态受到干扰，特别是在脊髓运动神经元中。我们最近表明，脊髓运动神经元含有过饱和的蛋白质组，因为它们的蛋白质浓度超过了它们的溶解度极限，导致有利于蛋白质错误折叠和聚集的亚稳定蛋白质组。最近的证据表明，神经元区室（如突触）内的亚稳定子蛋白质组可能特别脆弱，是其参与神经退行性疾病初始阶段的基础。为了研究运动神经元突触前终端是否具有亚稳定子蛋白质组，我们使用人类和小鼠脊髓运动神经元表达数据来计算过饱和度分数。在这里，我们发现人类和小鼠突触前终端的亚稳定蛋白质组的过饱和度分数都高于整个运动神经元蛋白质组。此外，我们观察到在 ALS 中下调的蛋白质在突触中过度表达。这些结果支持这样一种观点，即运动神经元突触前终端的亚稳定蛋白质组的不稳定性可能特别容易受到 ALS 中蛋白质稳态紊乱的影响，并可能有助于解释 ALS 中观察到的突触功能障碍。
