TDP-43 proteinopathies: a new class of proteinopathies

The recent identification of TAR-DNA-binding protein-43 (TDP-43) as the major component of the pathologic inclusions characteristic to sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), as well as most forms of amyotrophic lateral sclerosis (ALS), resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein in these conditions and provides further evidence that ALS and FTLD-U represent a clinicopathological spectrum of neurodegenerative disorders that share similar pathomechanisms. Although the physiological function of TDP-43 in the brain and its specific role in FTLD-U and ALS pathogenesis is currently unknown, the presence of ubiquitinated, hyperphosphorylated and truncated species of TDP-43, in addition to redistribution of physiological TDP-43 from the nucleus to cytoplasmic inclusions, implicates TDP-43 in a novel and unifying mechanism of neurodegeneration in TDP-43 proteinopathies. In this review, we summarize the identification of TDP-43 and the advances in understanding TDP-43 proteinopathies, and finally we discuss the implications of these discoveries for future strategies in developing diagnostics and therapeutics for FTLD-U and ALS.