ABSTRACT
The recent identification of the transactive response DNA binding protein with a molecular weight of 43 kDa (TDP-43) as the major pathological protein, in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), provides the new insight into understanding disease processes. The pathogenesis of both diseases is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. The number of degenerative diseases associated with TDP-43 has increased, leading to the new designation "TDP-43 proteinopathy". TDP-43 is a highly conserved protein ubiquitously expressed in many tissues including the central nervous system where it is present in neuronal and glial nuclei and to a lesser extent in the cytoplasm. Currently, TDP-43 has been implicated in regulating gene transcription and alternative splicing, in addition to maintaining mRNA stability. However, we still need to investigate the effects of posttranslational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage, on its regulation of various cellular processes. We review recently published studies of TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders and both ALS and FTLD-U are closely related conditions linked to similar mechanism of neurodegeneration.