FTLD with ubiquitin- and TDP-43-positive inclusions (FTLD-U)

Many cases of FTLD, even those without clinical evidence for ALS, show non-tau pathology (Neary et al, 2000), and many of these cases show ubiquitin-only (tau and a-synuclein negative) immunoreactive neuronal changes (FTLD-U). Recently, the identity of the ubiquitinated protein has been discovered: in FTLD-U, the TAR-DNA-binding protein 43 (TDP-43), which is normally contained within the nucleus, leaves the nucleus and accumulates in the cell bodies and processes of neurons (Neumann et al., 2006). TDP-43 has been identified in sporadic and familial FTLD-U and ALS cases, though subtle differences in the TDP-43 variants may reflect different pathogenic mechanisms in the different disease subtypes.