The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight? - PubMed (original) (raw)

Review

The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?

Rudolf C Hergesheimer et al. Brain. 2019.

Abstract

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.

Keywords: ALS; TDP-43; aggregation; neurodegeneration; therapeutics.

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Figures

Figure 1

Schematic diagram of the TDP-43 regions and domains. NES = nuclear export signal; Q/N = glutamine/asparagine.

Figure 2

Mechanisms of TDP-43 degradation and proposed therapeutic interventions. Autophagy (black sequence) (1) Nuclear, dimeric TDP-43 aberrantly accumulates in the cytoplasm. Degradation can occur to produce C-terminal fragments. (2) All TDP-43 forms enter the aggregation pathway (multi-colour arrows), in which the CTF is more active (thicker arrows), forming an oligomer and, finally, a poly-ubiquitinated aggregate. (3) Autophagy responds by engulfing the aggregate in an autophagosome, whose construction is essentially directed by ATG1 and ATG7 proteins. (4) The autophagosome fuses with the lysosome, creating the autolysosome in which the proteases degrade the aggregate, releasing peptides and free ubiquitin. In purple: rapamycin, berberine, tamoxifen, fluphenazine, trehalose stimulate the corresponding autophagic processes. The chaperone-mediated autophagy (CMA) sequence of the intrabody bound to the aggregate directs it to autophagy. UPS (blue sequence): Steps 1 and 2 are identical to those of autophagy. (3) The misfolded dimer and oligomer are now ubiquitinated and maintained by Hsp70 chaperones. (4) The ubiquitinated species are directed to the proteasome, where they are degraded. In purple: DNAJB1 stimulates Hsp70 activity. PABPN1 protects nuclear TDP-43 from cytoplasmic sequestration and increases UPS flux by an unknown mechanism. The PEST sequence of the intrabody directs the aggregate to the UPS. ELP (purple sequence): Events 1 and 2 are the same as in autophagy and the UPS. (3) The endocytic vesicle forms an early endosome that is largely regulated by Rab5. (4) This leads to the late endosome that can harbour material destined for degradation. For the sake of simplicity, we consider every form of TDP-43 to be a target for ELP. (5) The late endosome fuses with the lysosome, where the material is degraded. Autophagy and ELP have the ability to cooperate, because their pathways converge. Figure designed using image templates from Servier Medical Art (

https://smart.servier.com/image-set-download/

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The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight? - PubMed (original) (raw)