TDP-43 proteinopathies: a new class of proteinopathies

Abstract

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.

Keywords: :

• amyotrophic lateral sclerosis
• dementia
• frontotemporal dementia
• FTLD-U
• progranulin
• TDP-43
• ubiquitin

Financial disclosure

The authors have no relevant financial interests including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties related to this manuscript.