Miguel Laetitia, Avequin Tracey, Pons Marine, Frebourg Thierry, Campion Dominique, Lecourtois Magalie
Normandie University, UNIROUEN, Inserm, U1245, IRIB, Rouen, France.
Normandie University, UNIROUEN, Inserm, U1245, IRIB, Rouen, France; Department of Genetics, Rouen University Hospital, 76301 Rouen, France.
Brain Res. 2018 Sep 15;1695:1-9. doi: 10.1016/j.brainres.2018.05.021. Epub 2018 May 17.
TDP-43 is a major disease-causing protein in amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Today, >50 missense mutations in the TARDBP/TDP-43 gene have been described in patients with FTLD/ALS. However, the functional consequences of FTLD/ALS-linked TDP-43 mutations are not fully elucidated. In the physiological state, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. Maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells. In the present study, we investigated whether the FTLD/ALS-associated mutations could interfere with TDP-43 protein's capacity to modulate its own protein levels using Drosophila as an experimental model. Our data show that FTLD/ALS-associated mutant proteins regulate TDP-43 production with the same efficiency as the wild-type form of the protein. Thus, FTLD/ALS-linked TDP-43 mutations do not alter TDP-43's ability to self-regulate its expression and consequently of the homeostasis of TDP-43 protein levels.
TDP - 43是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTLD）中的一种主要致病蛋白。如今，已在FTLD/ALS患者中发现了超过50种TARDBP/TDP - 43基因的错义突变。然而，与FTLD/ALS相关的TDP - 43突变的功能后果尚未完全阐明。在生理状态下，TDP - 43的表达通过一个自调节负反馈环受到严格调控。维持正常的TDP - 43蛋白水平对于细胞的正常生理功能至关重要。在本研究中，我们以果蝇为实验模型，研究了与FTLD/ALS相关的突变是否会干扰TDP - 43蛋白调节自身蛋白水平的能力。我们的数据表明，与FTLD/ALS相关的突变蛋白调节TDP - 43产生的效率与该蛋白的野生型形式相同。因此，与FTLD/ALS相关的TDP - 43突变不会改变TDP - 43自我调节其表达的能力，进而不会改变TDP - 43蛋白水平的稳态。
