TDP-43 post-translational modifications in health and disease

• Published in: Expert opinion on therapeutic targets Vol. 22; no. 3; p. 279
• Main Author: Buratti, Emanuele
• Format: Journal Article
• Language: English
• Published: England 04.03.2018
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Amyotrophic Lateral Sclerosis - therapy; Animals; DNA-Binding Proteins - genetics; Down-Regulation; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - physiopathology; Frontotemporal Lobar Degeneration - therapy; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - physiopathology; Neurodegenerative Diseases - therapy; Protein Processing, Post-Translational; NPC; ALS; post-translational modifications; IBM; TDP-43; FTLD
• DOI: 10.1080/14728222.2018.1439923

Nuclear factor TDP-43 is a ubiquitously expressed RNA binding protein that plays a key causative role in several neurodegenerative diseases, especially in the ALS/FTD spectrum. In addition, its aberrant aggregation and expression has been recently observed in other type of diseases, such as myopathies and Niemann-Pick C, a lysosomal storage disease. Areas covered: This review aims to specifically cover the post-translational modifications (PTMs) that can affect TDP-43 function and cellular status both in health and disease. To this date, these include phosphorylation, formation of C-terminal fragments, disulfide bridge formation, ubiquitination, acetylation, and sumoylation. Recently published articles on these subjects have been reviewed in this manuscript. Expert opinion: Targeting aberrant TDP-43 expression in neurodegenerative diseases is a very challenging task due to the fact that both its overexpression and downregulation are considerably toxic to cells. This characteristic makes it difficult to therapeutically target this protein in a generalized manner. An alternative approach could be the identification of specific aberrant PTMs that promote its aggregation or toxicity, and developing novel therapeutic approaches toward their selective modification.