Weskamp Kaitlin, Barmada Sami J
Neuroscience Graduate Program and Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, United States.
Neuroscience Graduate Program and Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, United States.
Brain Res. 2018 Aug 15;1693(Pt A):67-74. doi: 10.1016/j.brainres.2018.01.015. Epub 2018 Jan 31.
The nuclear RNA-binding protein TDP43 is integrally involved in RNA processing. In accord with this central function, TDP43 levels are tightly regulated through a negative feedback loop, in which TDP43 recognizes its own RNA transcript, destabilizes it, and reduces new TDP43 protein production. In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), cytoplasmic mislocalization and accumulation of TDP43 disrupt autoregulation; conversely, inefficient TDP43 autoregulation can lead to cytoplasmic TDP43 deposition and subsequent neurodegeneration. Because TDP43 plays a multifaceted role in maintaining RNA metabolism, its mislocalization and accumulation interrupt several RNA processing pathways that in turn affect RNA stability and gene expression. TDP43-mediated disruption of these pathways-including alternative mRNA splicing, non-coding RNA processing, and RNA granule dynamics-may directly or indirectly contribute to ALS pathogenesis. Therefore, strategies that restore effective TDP43 autoregulation may ultimately prevent neurodegeneration in ALS and related disorders.
核RNA结合蛋白TDP43全面参与RNA加工过程。鉴于这一核心功能，TDP43的水平通过负反馈回路受到严格调控，在该回路中，TDP43识别其自身的RNA转录本，使其不稳定，并减少新的TDP43蛋白生成。在神经退行性疾病肌萎缩侧索硬化症（ALS）中，TDP43的细胞质错误定位和积累会破坏自身调节；相反，TDP43自身调节效率低下会导致细胞质TDP43沉积及随后的神经退行性变。由于TDP43在维持RNA代谢中发挥多方面作用，其错误定位和积累会中断多个RNA加工途径，进而影响RNA稳定性和基因表达。TDP43介导的这些途径的破坏——包括可变mRNA剪接、非编码RNA加工和RNA颗粒动态变化——可能直接或间接导致ALS发病机制。因此，恢复有效的TDP43自身调节的策略最终可能预防ALS及相关疾病中的神经退行性变。
