<i>TDP‐43</i> A315T mutation in familial motor neuron disease

Gitcho, Michael A.; Baloh, Robert H.; Chakraverty, Sumi; Mayo, Kevin H.; Norton, Joanne; Levitch, Denise; Hatanpaa, Kimmo J.; White, Charles L.; Bigio, Eileen H.; Caselli, Richard J.; Baker, Matt; Al‐Lozi, Muhammad; Morris, John C.; Pestronk, Alan; Rademakers, Rosa; Goate, Alison M.; Cairns, Nigel J.

doi:10.1002/ana.21344

Cited by 550 publications

(224 citation statements)

References 15 publications

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“…The recent discovery of multiple pathogenic TARDBP mutations in several FALS kindreds [13][14][15][16] further supports the importance of TDP-43 in the etiology and pathogenesis of ALS; however, unlike the A90V TDP-43 substitution, these recently identified TARDBP mutations are localized to the C-terminus of TDP-43 and thus, are likely to cause the disease through different mechanisms. Current literature suggests that the presence of disease segregating mutations in TDP-43 are rare, and to date, minimal neuropathological data from affected family members has been published.…”

Section: Resultsmentioning

confidence: 88%

“…These data provided compelling evidence that FTLD-U and ALS represent a clinicopathological spectrum of the same neurodegenerative disorder, i.e. TDP-43 proteinopathy, and this view is supported by the recent detection of several pathogenic TARDBP mutations in a number of FALS kindreds [13][14][15][16]. TDP-43, encoded by the TARDBP gene on chromosome 1, is a highly conserved, ubiquitously expressed nuclear protein implicated in repression of gene transcription, inhibition of exon splicing and interactions with splicing factors and nuclear bodies [17,18].…”

Section: Introductionmentioning

confidence: 72%

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A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

et al. 2008

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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). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

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Section: Resultsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 72%

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

et al. 2008

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“…These last two disorders have been directly linked to mutations in TDP-43 (9,10). In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases (11)(12)(13)(14).…”

mentioning

confidence: 99%

Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability

Caccamo

Majumder

Deng

et al. 2009

Journal of Biological Chemistry

143

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TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An ϳ25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous fulllength TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.TDP-43 (transactive response DNA-binding protein 43) is a conserved and ubiquitously expressed nuclear protein with a theoretical molecular mass of ϳ44 kDa. It is encoded by the TARDBP gene on chromosome 1, which is made of six exons that can be alternatively spliced to yield 11 different isoforms, with the mRNA encoding TDP-43 being the major species (1). Functionally, TDP-43 appears to be involved in exon skipping and alternative splicing (2, 3), and it has also been shown to link different types of nuclear bodies (4). Structural studies have confirmed the presence of two RNA recognition motifs (RRM1 and RRM2) and a glycine-rich C-terminal tail, which is thought to mediate protein-protein interaction (5).Recently, TDP-43 has been shown to be the major pathological protein in a wide range of disorders referred to as TDP-43 proteinopathies (6 -8). These include frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), 2 motor neuron disease, and amyotrophic lateral sclerosis (ALS). These last two disorders have been directly linked to mutations in TDP-43 (9, 10). In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases (11)(12)(13)(14). Sporadic and familial forms of FTLD-U and ALS are characterized by cytoplasmic accumulation of insoluble, hyperphosphorylated, ubiquitinated, and proteolytically cleaved C-terminal fragments in affected brain and spinal cord regions. The cytoplasmic accumulation of TDP-43 is associated with a de...

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“…Since than more than 120 different SOD1 mutations have been claimed responsible for 20 % of FALS cases (21). In 2008, Gitcho and colleagues (26) and Sreedharan and colleagues (27) independently reported pathogenic mutations in the TARDBP gene located on chromosome 1 encoding TAR DNA-binding protein 43 (TDP-43), which cause several neurodegenerative diseases such as FALS, sporadic ALS, and FTLD. Their findings support a direct role of TARDBP mutations in neurodegeneration.…”

Section: Geneticsmentioning

confidence: 99%

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

Liščić

2015

Archives of Industrial Hygiene and Toxicology

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS-and FTD-causing mutations known to date. TAR DNA-binding protein 43 , encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options. KEY WORDS: dementia; FTLD; FUS/TLS; genetics; motor neuron disease; TDP-43; C9ORF72 nucleotide repeat expansions; TARDBP Liščić RM, Molecular basis of ALS and FTD: Implications for translational studies Arh Hig Rada Toksikol 2015;66:285-290 Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders, which are characterised by decline in motor and cognitive functions, and short survival. ALS is clinically characterised by signs of upper and lower motor neuron degeneration and its progressive spread of signs within a region or to other regions in a time frame, as defined by the revised El Escorial criteria (1). Both diseases have fatal outcome within a few years' time (1). The cause is unknown and no effective treatment currently exists. There is a drug Riluzole, which slightly prolongs survival in patients with ALS (2), and a Phase II/III randomised, placebo-controlled trials of arimoclomol (BRX-345) in familial ALS with SOD-1 mutation (NCT00706147; www.clinicaltrials.gov). The substance arimoclomol may reduce the levels of protein aggregates in motor nerves, a possible cause of ALS, by boosting expression of chaperons Hsp 70 and Hsp 90 which help newly synthesised proteins properly fol...

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TDP‐43 A315T mutation in familial motor neuron disease

Cited by 550 publications

References 15 publications

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

Rapamycin Rescues TDP-43 Mislocalization and the Associated Low Molecular Mass Neurofilament Instability

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

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