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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology
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Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

机译：类似于Pri病毒的疾病中蛋白质的丰度降低和功能颠覆：获得的功能着迷但失去的功能影响病因

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Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins’ function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrPC, is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas.
机译：ions病毒已成为揭示神经元蛋白变性的许多方面的探路者。最近认识到几种主要的神经退行性疾病通过a病毒样机制传播，为诊断和治疗提供了新的可能性。因此，阿尔茨海默氏病和肌萎缩性侧索硬化症（ALS）中的关键蛋白，包括淀粉样β-前体蛋白，Tau和超氧化物歧化酶1（SOD1），以错误折叠的聚集形式扩散到相邻细胞，并表现出模板定向错误折叠，从而引起进一步的错误折叠。 ，破坏蛋白水解和毒性。在这里，我们将这种比较反过来，以问这些these病毒样疾病可以使我们了解广泛的病毒疾病类别，尤其是有关这些关键蛋白质错误折叠和聚集时功能的丧失。我们还考虑功能淀粉样蛋白是否可能揭示神经退行性疾病中颠覆蛋白功能的作用。我们的合成将SOD1识别为在functions病毒样蛋白质错误折叠过程中丧失的蛋白质功能的典范，因为SOD1本质上是不稳定的，并且以错误折叠的疾病相关形式丧失功能。在典型的ion病毒疾病中，这种方法的相似性被低估了，其中正常折叠的病毒蛋白PrP C 在致命的家族性失眠患者中以及在动物模型的临床前阶段，显然是通过蛋白抑制作用而大量减少机制。因此，虽然模板指导的错误折叠和传染性特性代表着使蛋白稳态研究人员着迷并定义is病毒（类）疾病所必需的功能获得，但神经退行性疾病中标志性蛋白质的功能丧失和颠覆仍需集成到有效治疗方法的设计中。我们提出实验以独特地测试这些想法。

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