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Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis
Trends in Neurosciences ( IF 15.9 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.tins.2020.03.002
Justin J Yerbury 1 , Natalie E Farrawell 1 , Luke McAlary 1
Affiliation  

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease but currently has no effective treatment. Growing evidence suggests that proteome homeostasis underlies ALS pathogenesis. Protein production, trafficking, and degradation all shape the proteome. We present a hypothesis that proposes all genetic lesions associated with ALS (including in mRNA-binding proteins) cause widespread imbalance to an already metastable proteome. The impact of such dysfunction is felt across the entire proteome and is not restricted to a small subset of proteins. Proteome imbalance may cause functional defects, such as excitability alterations, and eventually cell death. While this idea is a unifying principle for all of ALS, we propose that stratification will appear that might dictate the efficacy of therapeutics based on the proteostasis network.

中文翻译:

蛋白质组稳态功能障碍:ALS 发病机制的统一原理

肌萎缩侧索硬化症(ALS)是最常见的运动神经元疾病,但目前尚无有效的治疗方法。越来越多的证据表明蛋白质组稳态是 ALS 发病机制的基础。蛋白质的产生、运输和降解都塑造了蛋白质组。我们提出了一个假设,即所有与 ALS 相关的遗传损伤(包括 mRNA 结合蛋白)都会导致已经亚稳态的蛋白质组广泛失衡。这种功能障碍的影响遍及整个蛋白质组,而不仅限于一小部分蛋白质。蛋白质组失衡可能导致功能缺陷,例如兴奋性改变,并最终导致细胞死亡。虽然这个想法是所有 ALS 的统一原则,但我们认为分层的出现可能会决定基于蛋白质稳态网络的治疗效果。
更新日期:2020-05-01
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