Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118, and Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
J Neurosci. 2014 Mar 19;34(12):4167-74. doi: 10.1523/JNEUROSCI.2350-13.2014.
Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.
43kDa 转激活反应区(TAR)DNA 结合蛋白(TDP-43)是一种 RNA 结合蛋白,在家族性肌萎缩侧索硬化症(ALS)中发生突变。TDP-43 中的疾病相关突变增加了 TDP-43 聚集的倾向,导致应激颗粒的相应增加,应激颗粒是细胞质蛋白/RNA 复合物,在应激时形成。尽管该领域一直专注于应激颗粒,但 TDP-43 也形成其他类型的 RNA 颗粒。例如,TDP-43 与在神经元树突中普遍存在的 RNA 颗粒相关。由于 TDP-43 的聚集对于这些神经元 RNA 颗粒的形成也很重要,我们假设疾病相关突变即使在没有应激的情况下也可能改变颗粒的形成。我们现在报告 TDP-43(A315T 和 Q343R)中的 ALS 相关突变增加了大鼠海马神经元树突中神经元 TDP-43 颗粒的大小。这些突变相应地降低了颗粒的密度、运动和 TDP-43 颗粒的流动性。用 KCl 去极化大鼠海马神经元刺激 TDP-43 颗粒向树突迁移,但 A315T 和 Q343R TDP-43 颗粒迁移的距离较短,进入的树突较少,而野生型 TDP-43 则较少。这些发现突出了受疾病相关突变影响的 TDP-43 生物学的新元素,并提出了一种神经元选择性机制,通过该机制,TDP-43 突变可能引发神经元功能障碍。