TDP-43 Post-Translational Modifications in Health and Disease

Expert Opin Ther Targets. 2018 Mar;22(3):279-293. doi: 10.1080/14728222.2018.1439923. Epub 2018 Feb 20.

Abstract

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.

Keywords: ALS; FTLD; IBM; NPC; TDP-43; post-translational modifications.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 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

Substances

  • DNA-Binding Proteins
  • TDP-43 protein, human