We developed transgenic mice conditionally overexpressing human wild-type TDP-43 protein (hTDP-43-WT) in forebrain neurons, a model that recapitulates several key features of FTD.
Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases.
Here we demonstrate that another hnRNP family member, hnRNP E2, shows a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex and hippocampus of a subset of FTLD-TDP cases belonging to pathological subtypes A and C, where hnRNP E2 was found to co-localize with 87% of TDP-43 immunopositive inclusions. hnRNP E2-positive inclusions were not seen in FTLD-TDP cases with the <i>C9orf72</i> expansion or in any other neurodegenerative disorders examined.
We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls.
In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and contain certain RNA-binding proteins (RBPs), namely the TAR DNA-binding protein of 43 kDa (TDP-43) and the fused in sarcoma (FUS) gene product.
Transactive response DNA-binding protein of 43 kDa (TDP-43), an RNA and DNA binding protein involved in transcriptional repression, RNA splicing and RNA metabolism during the stress response, is the major component of neuronal inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD-TDP.
FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS.
The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP.
Insoluble, hyperubiquitylated TAR DNA binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases.
TAR DNA binding protein of 43 kDa (TDP-43) is the major pathological protein in almost all cases of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and ∼50% of frontotemporal lobar degeneration (FTLD), designated as FTLD-TDP.
: 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.
Mutations of the progranulin gene lead to progranulin haploinsufficiency and to frontotemporal lobar degeneration (FTD) with TDP-43 positive inclusions.
Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis.
Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia.
Defects in nucleocytoplasmic transport in FTD point to important commonalities in the pathogenic mechanisms of tau-mediated dementias and ALS-FTD due to TDP-43 and C9orf72 mutations.
The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP).
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.
These findings also document an association, in TDP43-proteinopathy patients, between heterogenous ribonucleoprotein pathology and RNA metabolism alterations and carry importance for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia.
TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia.
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).
Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP.