The finding of ubiquitin- and p62-positive, TDP-43-negative cytoplasmic inclusions in the hippocampus and neocortex suggests reclassification of the neuropathology of FTD-3 as a unique subtype of frontotemporal lobar degeneration with ubiquitin-positive inclusions that are TDP-43-negative.
: To develop therapeutic strategies to prevent FTD or delay its progression we must understand whether the loss of progranulin leads to the accumulation of TARDBP.
The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes.
TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS).
A number of families have been reported with autosomal dominant FTD-ALS linked to chromosome 9p and these also have TDP-43-positive frontotemporal lobar degeneration with ubiquitinated inclusions pathology.
TDP-43 was recently identified as the major pathological protein in sporadic amyotrophic lateral sclerosis and in the most common pathological subtype of frontotemporal dementia, frontotemporal lobar degeneration with ubiquitinated inclusions.
TDP-43 is now known to be a major component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and sporadic amyotrophic lateral sclerosis.
The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS).
Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions.
TAR DNA binding protein 43 (TDP-43) has been considered a signature protein in frontotemporal dementia and amyotrophic lateral sclerosis (ALS), but not in ALS associated with the superoxide dismutase 1 (SOD1) gene mutations (ALS1).
Thus, our results show that TDP-43 CTF expression recapitulates key biochemical features of pathological TDP-43 and support the hypothesis that the generation of TDP-43 CTFs is an important step in the pathogenesis of FTLD-U and ALS.
Advances in genetics and pathology have supported the idea of a continuum between frontotemporal dementia (FTD) and motor neurone disease (MND), which is strengthened by the discovery of the trans-activating responsive (Tar) sequence DNA binding protein (TDP-43) as a key component in the underlying pathology of FTD, FTD-MND and sporadic and familial MND patients.
Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS).
In this study we excluded mutations and copy number variations in the gene encoding TDP-43 (TARDBP) from an extended series of 173 FTD and 237 ALS patients.
The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein.