Department of Neurology, Neuromuscular Division, Washington University, Saint Louis, MO, USA.
Prion. 2011 Jan-Mar;5(1):1-5. doi: 10.4161/pri.5.1.14265. Epub 2011 Jan 1.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are clinically overlapping neurodegenerative disorders whose pathophysiology remains incompletely understood. ALS initiates in a discrete location, and typically progresses in a pattern consistent with spread of the degenerative process to involve neighboring regions of the motor system, although the basis of the apparent "spread" remains elusive. Recently mutations in two RNA binding proteins, TDP-43 and FUS, were identified in patients with familial ALS. In addition to being involved in numerous events related to RNA metabolism, each forms aggregates in neurons in ALS and FTLD. Recent evidence also indicates that both TDP-43 and FUS contain prion-related domains rich in glutamine (Q) and asparagine (N) residues, and in the case of TDP-43 this is the location of most disease causing mutations. This review discusses the potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression in ALS and FTLD.
肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）是临床重叠的神经退行性疾病，其发病机制仍不完全清楚。ALS 起始于一个离散的位置，并且通常按照退行性过程向运动系统的相邻区域扩散的模式进展，尽管明显的“扩散”的基础仍然难以捉摸。最近，在家族性 ALS 患者中发现了两种 RNA 结合蛋白，TDP-43 和 FUS 的突变。除了参与与 RNA 代谢相关的许多事件外，每种蛋白在 ALS 和 FTLD 的神经元中形成聚集体。最近的证据还表明，TDP-43 和 FUS 都含有富含谷氨酰胺（Q）和天冬酰胺（N）残基的朊病毒相关结构域，在 TDP-43 的情况下，大多数致病突变都位于该位置。这篇综述讨论了 TDP-43 和 FUS 中的朊病毒相关结构域在 ALS 和 FTLD 中的正常生理学、病理性聚集和疾病进展中的潜在相关性。
