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Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation

Abstract

Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease.

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Fig. 1: TDP43 protein structure.
Fig. 2: Mechanisms of TDP43 autoregulation.
Fig. 3: Nucleocytoplasmic transport and diffusion of TDP43.
Fig. 4: Phase transition of TDP43.
Fig. 5: Mechanisms of TDP43 control.

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Acknowledgements

The authors thank somersault18:24 for valuable assistance with figure assembly and design. P.T. thanks M. Kalthoff for helpful discussions during the preparation of the manuscript. Research by P.T. and L.V.D.B. is supported by VIB, KU Leuven (C1 and Opening the Future Fund), the Fund for Scientific Research Flanders (FWO-Vlaanderen), the Thierry Latran Foundation, the Association Belge contre les Maladies neuro-Musculaires (ABMM), the Muscular Dystrophy Association (MDA), the Association Française contre les Myopathies (AFM), Target ALS, the ALS Liga België (A Cure for ALS) and the ALS Association (ALSA). P.T. is a PhD fellow of FWO-Vlaanderen (11C7621N). F.H. acknowledges support from the UK Medical Research Council (G0701498; MR/L010666/1), the MND Association (Hirth/Nov15/914-793; Hirth/Oct13/6202; Hirth/Mar12/6085; Hirth/Oct07/6233) and Alzheimer’s Research UK (Hirth/ARUK/2012).

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P.T. and F.H. wrote the manuscript and all authors made substantial contributions to the discussion of the content and reviewed and edited the article.

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Correspondence to Ludo Van Den Bosch or Frank Hirth.

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Nature Reviews Neuroscience thanks E. Buratti, C. Lagier-Tourenne and J. Ule (who co-reviewed with M. Hallegger) for their contribution to the peer review of this work.

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Glossary

Heterogeneous nuclear ribonucleoprotein

(hnRNP). An RNA-binding protein involved in several aspects of nucleic acid metabolism such as transcriptional and translational regulation, alternative splicing and mRNA stabilization.

Splicing

A form of processing of a newly synthesized precursor mRNA transcript during which introns are removed and exons are joined together, thereby transforming it into a mature mRNA.

Proteinaceous inclusions

Aggregates of one or more proteins found in the nucleus and/or the cytoplasm, a main characteristic of many neurodegenerative diseases.

Aggregates

Accumulations of misfolded and/or intrinsically disordered proteins that form amyloid-like fibrils and insoluble depositions in the nucleus and/or the cytoplasm and are highly associated with neurodegeneration and pathology.

Low-complexity domain

An intrinsically disordered protein sequence that is unable to form orderly 3D structures, such as α-helices or β-strands, and is thus prone to intermolecular interactions and involved in phase separation and the formation of pathological aggregates.

Stress granules

Membraneless organelles formed upon cellular stress by liquid demixing and accumulation of RNA and proteins.

Phase separation

The creation of two different phases from a homogeneous mixture, which can occur by liquid demixing of soluble monomeric proteins and includes their dispersion into liquid droplets and accumulation into irreversible cytoplasmic aggregates.

Polymorphs

Proteins whose sequences enable them to adopt different structural conformations.

Cellular stress

A consequence of environmental or chemical stressors, such as extreme temperatures, alterations in pH or exposure to toxins, that threatens the internal state and, ultimately, the survival of a cell.

Cryptic exons

Coding sequences within a precursor mRNA that are normally not included in the mature RNA but can occur in an alternative form of the mRNA.

Nonsense-mediated decay

A surveillance and degradation mechanism in eukaryotes, mainly eliminating mRNAs containing premature stop codons.

Alternative polyadenylation

A process of gene regulation leading to the production of mRNA isoforms in which the formation of poly(A) tails is initiated at different positions in the precursor mRNA.

RNA exosome

A ring-structured multi-protein complex found in the cytoplasm, nucleus or nucleolus, responsible for degrading different kinds of RNA molecules.

Molecular chaperones

Proteins that assist in the correct and timely folding or unfolding of other proteins or the assembly and disassembly of macromolecular complexes.

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Tziortzouda, P., Van Den Bosch, L. & Hirth, F. Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation. Nat Rev Neurosci 22, 197–208 (2021). https://doi.org/10.1038/s41583-021-00431-1

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