TDP-43 proteinopathies: a new wave of neurodegenerative diseases
Eva Maria Johanna de Boer, Viyanti K Orie, Timothy L. 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, Steve Vucic
Abstract
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.