FTLD/ALS-linked TDP-43 mutations do not alter TDP-43’s ability to self-regulate its expression in Drosophila

• Published in: Brain research 2018-09, Vol.1695, p.1-9
• Main Authors: Miguel, Laetitia, Avequin, Tracey, Pons, Marine, Frebourg, Thierry, Campion, Dominique, Lecourtois, Magalie
• Format: Article
• Language: English
• Subjects: ALS; Autoregulation; Drosophila; FTLD; Life Sciences; Mutation; Neurons and Cognition; TDP-43
• ISSN: 0006-8993; 1872-6240; 0006-8993
• DOI: 10.1016/j.brainres.2018.05.021

•FTLD/ALS-associated mutant TDP-43 proteins regulate TDP-43 production.•TDP-43 mutations do not alter TDP-43’s ability to self-regulate its expression.•TDP-43 mutant forms regulate TDP-43 mRNA steady-state levels. 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.