The Debated Toxic Role of Aggregated TDP-43 in Amyotrophic Lateral Sclerosis: A Resolution in Sight?

Brain, Volume 142, Issue 5, May 2019, Pages 1176–1194

Rudolf C. Hergesheimer1*, Anna A. Chami1*, Denis Reis de Assis1, Patrick Vourc’h1,2, Christian R. Andres1,2, Philippe Corcia1,3, Débora Lanznaster1#, Hélène Blasco1, 2


1 UMR 1253, iBRAIN, Université de Tours, INSERM, Tours, France.

2 CHU de Tours, Service de Biochimie et Biologie Moléculaire, Tours, France.

3 CHU de Tours, Service de Neurologie, Tours, France.

* These authors contributed equally to the manuscript


Transactive Response DNA-Binding Protein-43 (TDP-43) is an RNA/DNA binding protein that forms phosphorylated and ubiquitinated aggregates in the cytoplasm of motor neurons in Amyotrophic Lateral Sclerosis (ALS), which is a hallmark of this disease. ALS is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of ALS, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death. In this review, we attempt to reconcile the current literature surrounding this debate by discussing the results and limitations of the published data relating TDP-43 aggregates to cytotoxicity, as well as therapeutic perspectives of TDP-43 aggregate clearance. We point out key data suggesting that the formation of TDP-43 aggregates and the capacity to self-template and propagate among cells as a “prion-like” protein, another pathological property of TDP-43 aggregates, are a significant cause of motor neuronal death. We discuss the disparities among the various studies, particularly with respect to the type of models and the different forms of TDP-43 utilized to evaluate cellular toxicity. We also examine how these disparities can interfere with the interpretation of the results pertaining to a direct toxic effect of TDP-43 aggregates. Furthermore, we present perspectives for improving models in order to better uncover the toxic role of aggregated TDP-43. Finally, we review the recent studies on the enhancement of the cellular clearance mechanisms of autophagy, the ubiquitin proteasome system, and endocytosis in an attempt to counteract TDP-43 aggregation-induced toxicity. Altogether, the data available so far encourage us to suggest that the cytoplasmic aggregation of TDP-43 is key for the neurodegeneration observed in motor neurons in ALS patients. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for ALS management.


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