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TDP-43 proteinopathies: A new wave of neurodegenerative diseases

Lookup NU author(s): Dr Timothy Williams, Professor Mark BakerORCiD, Dr Tuomo Polvikoski



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (∼45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Publication metadata

Author(s): De Boer EMJ, Orie VK, Williams T, Baker MR, Oliviera H, Polvikoski T, Silsby M, Menon P, Van Den Bos M, Halliday GM, Van Den Berg LH, Van Den Bosch L, Van Damme P, Kiernan M, Van Es MA, Vucic S

Publication type: Review

Publication status: Published

Journal: Journal of Neurology, Neurosurgery and Psychiatry

Year: 2021

Volume: 92

Issue: 1

Pages: 86-95

Print publication date: 15/12/2020

Online publication date: 11/11/2020

Acceptance date: 11/09/2020

ISSN (print): 0022-3050

ISSN (electronic): 1468-330X

Publisher: BMJ Publishing Group


DOI: 10.1136/jnnp-2020-322983