TDP-43—The key to understanding amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration leading to progressive muscle atrophy, weakness, paralysis and death. The majority of ALS (>95%) shows intracellular aggregation of transactive response DNA binding protein (TDP-43) as a prominent pathological feature. TDP-43 is normally a nuclear protein. In ALS, TDP-43 accumulates and aggregates in the cytoplasm (thus forming TDP-43 proteinopathy) and is depleted from the nucleus in CNS cells, including motor neurons and glia. While TDP-43 aggregation can harm cells through a gain of toxicity, it can also cause a loss of TDP-43 function in conjunction with its nuclear depletion. TDP-43 regulates its own expression to maintain itself at a constant level. Perturbation of this level by either increasing or decreasing TDP-43 in animal models leads to neurodegeneration and ALS phenotypes. The evidence supports the hypothesis that TDP-43 dysfunction is a critical driver of neurodegeneration in the vast majority of ALS cases.

Keywords:

• FTD
• FTLD
• frontotemporal dementia
• gain of function
• loss of function
• motoneuron
• neurological disease

This article refers to:

Acknowledgments

The authors are grateful to Dr. Daryl Bosco for critically reading and editing the manuscript.

Additional information

Funding

This work was supported by grants from the ALS Association to Z.X.