The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies.
The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies.
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DOI：
10.1038/s12276-020-00513-7
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发表时间：
2020-10
影响因子：
12.8
通讯作者：
Kim HJ
中科院分区：
文献类型：
--
作者：
Jo M;Lee S;Jeon YM;Kim S;Kwon Y;Kim HJ
TAR DNA结合蛋白43（TDP-43）是一种高度保守的核RNA/DNA结合蛋白，参与RNA加工的调控。TDP-43聚集体在中枢神经系统中的积累是许多神经退行性疾病的共同特征，例如肌萎缩性侧索硬化症（ALS）、额颞叶痴呆（FTD）、阿尔茨海默病（AD）和边缘系统主导的年龄相关TDP-43脑病（LATE）。越来越多的证据表明，由tau、淀粉样蛋白-β和α-突触核蛋白组成的异常蛋白聚集体的朊病毒样扩散参与了神经退行性疾病（如AD和PD）的进展。与朊病毒样蛋白相似，TDP-43的病理性聚集体可以以种子依赖性和自模板方式在细胞间转移。在这里，我们回顾临床和实验研究支持朊病毒样传播的错误折叠TDP-43，并讨论这些病理性聚集蛋白的传播的分子机制。错误折叠的TDP-43以朊病毒样方式在细胞之间传播的想法可能会指导TDP-43相关神经退行性疾病的新治疗策略。需要进一步的研究来确定几种神经退行性疾病常见的聚集体形成蛋白如何在整个大脑中传播。许多神经退行性疾病涉及由“朊病毒样”蛋白质产生的聚集体，这些蛋白质是错误折叠的蛋白质，可以将其异常结构赋予相邻的健康蛋白质，导致聚集体像感染一样传播。韩国大邱韩国脑研究所的Hyung-Jun Kim及其同事回顾了目前对交互反应DNA结合蛋白43（TDP-43）的理解，TDP-43是一种与阿尔茨海默病和额颞叶痴呆症等疾病有关的聚集形成蛋白。越来越多的证据表明，TDP-43可能以朊病毒样方式传播。TDP-43与阿尔茨海默病的发病有关，错误折叠的TDP-43聚集体的传播与疾病的严重程度密切相关。需要更多的研究来了解TDP-43如何在不同的组织和中枢神经系统细胞中传播。
TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases. Further research is needed to determine how an aggregate-forming protein common to several neurodegenerative disorders propagates throughout the brain. Many neurodegenerative conditions involve aggregates created by ‘prion-like’ proteins, misfolded proteins that can confer their abnormal structure on neighboring healthy proteins, resulting in aggregates which spread rather like an infection. Hyung-Jun Kim at the Korea Brain Research Institute in Daegu, South Korea, and co-workers reviewed current understanding of the transactive response DNA-binding protein 43 (TDP-43), an aggregate-forming protein implicated in disorders such as Alzheimer’s disease and frontotemporal dementia. Growing evidence suggests that TDP-43 may spread in a prion-like fashion. TDP-43 is implicated in the onset of Alzheimer’s, and the spread of misfolded TDP-43 aggregates is closely tied to disease severity. More research is needed into how TDP-43 propagates in different tissues and central nervous system cells.
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