Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy.,Journal of Molecular Biology

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Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy.
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2020-02-29 , DOI: 10.1016/j.jmb.2020.02.018
Rebecca L Casterton ₁ , Rachel J Hunt ₁ , Manolis Fanto ₂

Affiliation

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) constitute aggressive neurodegenerative pathologies that lead to the progressive degeneration of upper and lower motor neurons and of neocortical areas, respectively. In the past decade, the identification of several genes that cause these disorders indicated that the two diseases overlap in a multifaceted spectrum of conditions. The autophagy-lysosome system has been identified as a main intersection for the onset and progression of neurodegeneration in ALS/FTD. Genetic evidence has revealed that several genes with a mechanistic role at different stages of the autophagy process are mutated in patients with ALS/FTD. Moreover, the three main proteins aggregating in ALS/FTD, including in sporadic cases, are also targeted by autophagy and affect this process. Here, we examine the varied dysfunctions and degrees of involvement of the autophagy-lysosome system that have been discovered in ALS/FTD. We argue that these findings shed light on the pathological mechanisms in the ALS/FTD spectrum and conclude that they have important consequences both for treatment options and for the basic biomolecular understanding of how this process intersects with RNA metabolism, the other major cellular process reported to be dysfunctional in part of the ALS/FTD spectrum.

中文翻译：

肌萎缩性侧索硬化症和额颞痴呆疾病谱中的致病机制异质性：通过自噬的镜头提供焦点。

肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）构成侵略性神经退行性病变，分别导致上，下运动神经元和新皮层区域逐渐退化。在过去的十年中，对导致这些疾病的几种基因的鉴定表明，这两种疾病在多种情况下重叠。自噬-溶酶体系统已被确定为ALS / FTD中神经变性的发生和发展的主要交叉点。遗传证据表明，在ALS / FTD患者中，在自噬过程不同阶段具有机械作用的几个基因发生了突变。此外，在ALS / FTD中聚集的三种主要蛋白质（包括在偶发情况下）也被自噬靶向，并影响这一过程。这里，我们检查了在ALS / FTD中发现的自噬-溶酶体系统的各种功能障碍和受累程度。我们认为，这些发现揭示了ALS / FTD谱中的病理机制，并得出结论，它们对治疗选择以及对该过程与RNA代谢如何相交的基本生物分子理解都具有重要意义，其他主要的细胞过程据报道在部分ALS / FTD频谱中功能失调。

更新日期：2020-02-29

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