Mutations in the GRN gene coding for progranulin (PGRN) are responsible for many cases of familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP-43)-positive inclusions (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.
In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9).
However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72.
Mutations in the gene <i>TARDBP</i>, which encodes TAR DNA-binding protein 43 (TDP-43), are a rare cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed.
Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.
Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases.
Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey.
Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS).
We analysed the expression and localization of familial ALS-causing proteins, including transactive response DNA binding protein-43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), Cu/Zn superoxide dismutase (SOD1) and optineurin (OPTN) by immunohistochemistry.
The RNA-binding proteins, TDP-43 and FUS, are principal components of cytoplasmic inclusions found in motor neurons of ALS patients and mutations in TDP-43 and FUS are linked to familial and sporadic ALS.
Mutations in the transactive response DNA binding protein-43 (TARDBP/TDP-43) gene, which regulates transcription and splicing, causes a familial form of amyotrophic lateral sclerosis (ALS).
For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS.
French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature.
The RNA/DNA-binding proteins fused in sarcoma (FUS; also known as TLS) and TAR DNA binding protein-43 (TDP-43) have recently been shown to be genetically and pathologically associated with familial forms of ALS and FTD.
Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP).
The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis.