Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum.
Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum.
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DOI：
10.3389/fnmol.2017.00119
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发表时间：
2017
影响因子：
4.8
通讯作者：
Atkin JD
中科院分区：
文献类型：
--
作者：
Shahheydari H;Ragagnin A;Walker AK;Toth RP;Vidal M;Jagaraj CJ;Perri ER;Konopka A;Sultana JM;Atkin JD
蛋白质稳态在细胞功能中具有重要的调节作用。蛋白质质量控制机制，包括蛋白质折叠和蛋白质降解过程，在有丝分裂后的神经元中具有至关重要的功能。细胞蛋白质质量控制依赖于多种策略，包括分子伴侣、自噬、泛素蛋白酶体系统、内质网（ER）相关降解（ERAD）和应激颗粒（SG）的形成，以调节蛋白质稳态。神经退行性疾病的特征在于存在错误折叠的蛋白质聚集体，这意味着蛋白质质量控制机制在这些条件下功能失调。肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是神经退行性疾病，现在被认为是重叠的临床和病理学，形成一个连续的疾病谱。在这篇综述文章中，我们通过讨论ALS和/或FTD中涉及的主要蛋白质，详细介绍了整个ALS-FTD连续体中蛋白质质量控制机制失调的证据。我们还讨论了在这些疾病中治疗靶向蛋白质质量机制的可能方法，并强调了有前途的基于蛋白质质量控制的临床试验疗法。
Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.