TDP-43 (also known as TARDBP) is a pathological signature protein of neurodegenerative diseases, with TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD)-TDP and amyotrophic lateral sclerosis (ALS)-TDP.
The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS.
TDP-43 has been identified as a major component of ubiquitin-positive tau-negative cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS).
Defining a cellular signature of aggregated TDP-43 common to nearly all MND and a large proportion of frontotemporal dementia (FTD), has placed MND alongside more traditional cerebral neurodegeneration.
Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries.
<b>Background:</b> The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a <i>C9orf72</i> mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions.
Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process.
Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS).
(1) Degeneration of white matter in sporadic FTLD-TDP was characterized by increased vacuolation and GI, (2) pathological changes were topographically distributed, which suggests propagation of pathological TDP-43 in specific groups of fibers, and (3) both white matter pathology and gray matter pathology need to be considered to quantify the pathological "load" in FTLD-TDP..
We describe novel transactivation response DNA-binding protein of 43 kd (TDP-43)-positive structures in the brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions and familial Lewy body disease.
Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity.
A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the 'charged multivesicular body protein 2B' (CHMP2B), the 'FUS RNA binding protein' (FUS), the 'TAR DNA binding protein' (TARDBP), the 'sequestosome1' (SQSTM1), and the 'valosin containing protein' (VCP).
However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations.
These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies.
TDP-43 (transactive- response DNA binding protein) amazes structural biologist as its aberrant ubiquitinated cytosolic inclusions is largely involved in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients [corrected] .