Shahheydari Hamideh, Ragagnin Audrey, Walker Adam K, Toth Reka P, Vidal Marta, Jagaraj Cyril J, Perri Emma R, Konopka Anna, Sultana Jessica M, Atkin Julie D
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie UniversitySydney, NSW, Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe UniversityMelbourne, VIC, Australia.
Front Mol Neurosci. 2017 May 10;10:119. doi: 10.3389/fnmol.2017.00119. eCollection 2017.
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.
蛋白质稳态，即蛋白稳态，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，在有丝分裂后神经元中具有关键功能。细胞蛋白质质量控制依赖多种策略，包括分子伴侣、自噬、泛素蛋白酶体系统、内质网相关降解（ERAD）以及应激颗粒（SGs）的形成，以调节蛋白稳态。神经退行性疾病的特征是存在错误折叠的蛋白质聚集体，这意味着在这些情况下蛋白质质量控制机制功能失调。肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是神经退行性疾病，目前已认识到它们在临床和病理上相互重叠，形成一个连续的疾病谱。在这篇综述文章中，我们通过讨论与ALS和/或FTD相关的主要蛋白质，详细阐述了在整个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蛋白质质量机制可能的治疗靶点，并强调了有前景的基于蛋白质质量控制的临床试验治疗方法。
