[TDP-43 proteinopathies: ALS and frontotemporal dementias]

Both, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), and their combination (FTLD-U/MND) are principally sporadic diseases that are rarely familial. Cytoplasmic ubiquitinated proteinaceous inclusions in motor and extra-motor neurons are the pathological hallmark of all three forms. In 2006, the TAR DNA-binding protein of 43 kDa (TDP-43) was both identified as the key protein component of the ubiquitinated inclusions and recognised as the key protein of a spectrum of diseases that have since been consolidated as TDP-43 proteinopathies. TDP-43 as a nuclear protein contributes to the regulation of gene expression, and associated with neurodegeneration, it has been found to be truncated, hyperphosphorylated, and mislocalized. It is unclear whether the loss of the TDP-43's nuclear function or the gain of a toxic function outside its nucleus is disease causing. Since 2008, several TARDBP-mutations have been identified as leading to the autosomal-dominant familial ALS (ALS 10), although no TARDBP-mutations have yet to be linked to FTLD.