Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis.
Genotype-property patient-phenotype relations suggest that proteome exhaustion can cause amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pone.0118649
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kepp KP
中科院分区：
文献类型：
--
作者：
Kepp KP
迟发性神经退行性疾病仍然知之甚少的搜索继续感知的致病蛋白质种类。以前，发现引起肌萎缩侧索硬化症（ALS）的超氧化物歧化酶1（SOD 1）的变体使净电荷不稳定并减少，这表明了致病性聚集机制。本文报告了对汇编的患者数据以及人类SOD 1变体（ALS的主要危险因素）的实验和计算蛋白质特性的分析。稳定性和减少的净电荷与疾病显著相关，比以前观察到的更大的意义。使用两种独立的方法和两个数据集，发现ALS引起的突变与所有可能的2907个SOD 1突变共享平均稳定性的概率< 3%（t-统计检验）。最重要的是，未加权的患者存活时间与错误折叠/未折叠蛋白质拷贝数密切相关，表示为实验稳定性的指数函数（R 2 = 0.31，p = 0.002），并且该表型因电荷而进一步恶化（R 2 = 0.51，p = 1.8 x 10−5）。这一发现表明疾病与错误折叠蛋白质的拷贝数有关。由于错误折叠的蛋白质拷贝的昂贵的蛋白质周转导致的运动神经元的耗竭与数据一致，但可以进一步解释例如SOD 1致病性的表达依赖性、缺乏分子毒性模式的鉴定、散发性ALS中SOD 1 mRNA水平升高、ALS患者中生物能量效应和静息能量消耗增加、影响RNA代谢的遗传风险因素、以及最近的发现，当蛋白酶体抑制剂洗脱后蛋白酶体活性恢复时，SOD 1突变体变得有毒。蛋白质组耗竭也与产生能量的线粒体在ALS通常起始的神经肌肉接头处积累一致。如果是真的，这种衰竭机制意味着ALS治疗的重点完全改变，积极护理运动神经元的能量状态和蛋白质周转。
Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability < 3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R 2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R 2 = 0.51, p = 1.8 x 10−5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e.g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons.
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作者：
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通讯作者：
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影响因子：
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DOI：
10.1039/c2mt20052j
发表时间：
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期刊：
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影响因子：
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