TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target

ABSTRACT

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that lacks an effective treatment. Aggregates of the TAR DNA-binding protein-43 (TDP-43) are observed in 97% of all ALS cases, thus making this protein a major therapeutic target in ALS. 

Areas covered

The authors describe the major cellular functions of TDP-43 and the features and consequences of TDP-43 proteinopathy. Drawing from fundamental and preclinical studies on cellular and animal TDP-43 models of ALS and selected clinical trials, the major pathways that have been targeted for the mitigation of TDP-43 pathology in ALS are discussed. The authors provide insights on the approaches targeting the tendency of TDP-43 for aggregation, defective nucleocytoplasmic transport, dysfunctional proteostasis, abnormal stress granule dynamics, and pathological post-translational modifications of TDP-43.

Expert opinion

The complexity of ALS and TDP-43 proteinopathy generates challenges for the development of novel therapeutic approaches. However, the critical involvement of TDP-43 in the initiation and progression of ALS, makes it a promising therapeutic target. Further research should be centered on the development of precision strategies, consideration of patient subgroups, the prevention of the mislocalization of TDP-43 and restoration of the lost functions of TPD-43. 

KEYWORDS:

• Aggregation
• ALS
• mislocalization
• neurodegeneration
• proteinopathy
• TDP-43
• therapeutics

Article highlights

• TDP-43 plays a major role in the initiation and progression of ALS and hence is a promising therapeutic target. 

• TDP-43 is crucial for cellular homeostasis, particularly in motoneurons where it plays a key role in the processing of mRNA, the biogenesis of miRNA, mitochondrial function, the cellular response to stress, and axonal transport.  

• TDP-43 proteinopathy seems to be mainly mediated by the loss of the protein’s normal function and autoregulation, which are due to its nuclear depletion and cytoplasmic aggregation.  

• Most therapeutic approaches indirectly target TDP-43 by regulating nucleocytoplasmic transport and nuclear functions of TDP-43, the cellular response to stress, RNA-TDP-43 interactions, the degradation pathways of the cell, and the post-translational modifications of TDP-43.  

• TDP-43-specific fragments of antibodies are recently being developed to directly target pathological TDP-43 for degradation.  

• It is important to determine which mechanism of TDP-43 pathology (e.g. loss of nuclear function, aggregation, cytoplasmic mislocalization, etc.) should be targeted to obtain the best therapeutic effects with the least potential side effects. 

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Acknowledgments

LabEx MAbImprove, ARD CVL biopharmaceuticals, Région Centre Val de Loire.

Disclosure statement

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This paper was not funded.