• Eva Maria Johanna de Boer, Viyanti K Orie, Timothy Williams, Mark R Baker, Hugo M De Oliveira, Tuomo Polvikoski, Matthew Silsby, Parvathi Menon, Mehdi van den Bos, Glenda M Halliday, Leonard H van den Berg, Ludo Van Den Bosch, Philip van Damme, Matthew C Kiernan, Michael A van Es, and Steve Vucic.
• Department of Neurology, Brain Centre Rudolf Magnus, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
• J. Neurol. Neurosurg. Psychiatr. 2020 Nov 11; 92 (1): 869586-95.

AbstractInclusions 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.© 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.

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