TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander

Abstract

In 2006 the protein TDP-43 was identified as the major ubiquitinated component deposited in the inclusion bodies found in two human neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenesis of both disorders is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. Now, in 2008, several papers have been published in quick succession describing mutations in the TDP-43 gene, showing they can be a primary cause of amyotrophic lateral sclerosis. There are many precedents in neurodegenerative disease in which rare single-gene mutations have given great insight into understanding disease processes, which is why the TDP-43 mutations are potentially very important.

Fig. 1

TDP-43 mutations in ALS. TDP-43 is encoded by a 6-exon gene, of which exons 2-6 are protein coding (top). The TDP-43 protein contains four known functional domains: a nuclear localization sequence, two central RNA Recognition Motifs (RRM1 and RRM2), and a C-terminal glycine-rich domain, predicted to mediate protein-protein interactions. All disease mutations so far are found in the glycine-rich domain (encoded by exon 6), with the exception of one mutation in RRM1 (encoded by exon 4). A mutation in the nuclear localization domain has been reported in two unaffected controls (data compiled from Gitcho et al. ; Kabashi et al. ; Sreedharan et al. ; Van Deerlin et al. ; Yokoseki et al. 2008)