TDP-43 post-translational modifications in health and disease

ABSTRACT

Introduction: 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:

• TDP-43
• ALS
• FTLD
• NPC
• IBM
• post-translational modifications

Article Highlights

• Nuclear factor TDP-43 plays a major role in several neurodegenerative diseases, especially in the ALS/FTD spectrum.

• Its aberrant aggregation and mislocalization is associated with the presence of several post-translational modifications (PTMs) that can influence its functionality and cellular status.

• At present, TDP-43 PTMs include phosphorylation, formation of C-terminal fragments, disulphide bridge formation, ubiquitination, acetylation, and sumoylation.

• Targeting specific PTM events that promote its aberrant aggregation or toxicity can represent an important research topic for developing novel therapeutic approaches.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work is supported by the International Scientific Co-operation Agreement between Italy and Israel program (SCREENCELLS4ALS, Ministero Affari Esteri, MAE, Italy).