The Debated Toxic Role of Aggregated TDP-43 in Amyotrophic Lateral Sclerosis

A Resolution in Sight?

Rudolf C. Hergesheimer; Anna A. Chami; Denis Reis de Assis; Patrick Vourc'h; Christian R. Andres; Philippe Corcia; Débora Lanznaster; Hélène Blasco


Brain. 2019;142(5):1176-1194. 

In This Article

Abstract and Introduction


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, which is a hallmark of this disease. Amyotrophic lateral sclerosis is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of amyotrophic lateral sclerosis, 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 used 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 patients with amyotrophic lateral sclerosis. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for amyotrophic lateral sclerosis management.


Transactive response DNA Binding Protein 43 (TDP-43, 43 kDa) is a ubiquitous protein encoded by the TARDBP gene, which is highly conserved throughout different species (e.g. Caenorhabditis elegans, Drosophila melanogaster, mammals, etc.). TDP-43 is essential for the development of the CNS from the earliest stages of embryonic life to adulthood (Huang et al., 2010; Sephton et al., 2010) and preferentially binds RNA UG motifs (Tollervey et al., 2011; Xiao et al., 2011). TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family and is implicated in multiple steps of transcriptional and post-transcriptional regulation (Nakielny and Dreyfuss, 1997; Krecic and Swanson, 1999; Dreyfuss et al., 2002; Prasanth et al., 2005; Martinez-Contreras et al., 2007; He and Smith, 2009; Busch and Hertel, 2012). Under physiological conditions, the majority of TDP-43 is nuclear, while a small proportion is continuously shuttled between the nucleus and cytoplasm. In the nucleus, the functions of TDP-43 include the repression of gene expression, pre-mRNA splicing, and autoregulation of its own mRNA (Ayala et al., 2008, 2011b). TDP-43 also regulates miRNA biogenesis through its interaction with the Drosha-containing protein complex (Kawahara and Mieda-Sato, 2012). In the cytoplasm under stress conditions, TDP-43 controls mRNA stability, translation, and nucleocytoplasmic transport by forming cytoplasmic ribonucleoprotein complexes, termed stress granules (Zhao et al., 2018).

An ever-increasing number of research groups report the presence of TDP-43-enriched cytoplasmic aggregates in diverse neuropathological conditions. Since the 1990s, it has been shown that the presence of ubiquitin-positive and tau-negative cytoplasmic aggregates is a common pathological feature in the motor neurons of patients suffering from amyotrophic lateral sclerosis (ALS) and in the frontal and temporal lobes in patients with frontotemporal lobar degeneration (FTLD) (Okamoto et al., 1990; Kwong et al., 2007). Pathological TDP-43 has been found to be depleted from the nucleus and sequestered in insoluble, cytoplasmic aggregates in post-mortem neural tissue, suggesting that the nucleo-cytoplasmic relocation is involved in pathogenic aggregation (Arai et al., 2006; Neumann et al., 2006; Winton et al., 2008). Full-length and fragmented TDP-43 are the major components of these aggregates in the brains and motor neurons of ALS patients. Currently, TDP-43 aggregates are considered the histopathological hallmark of ALS.

However, it has remained debatable as to whether this aggregation causes motor neuronal degeneration. In this review, we explore the main findings that highlight the cytotoxicity of TDP-43 aggregation. Moreover, we discuss the structural properties of TDP-43 that underlie its propensity to aggregate and suggest novel therapeutic interventions that could decrease TDP-43 aggregation and mitigate the debilitating neurodegeneration of ALS.