TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Deerlin, Vivianna M. Van; Leverenz, James B.; Bekris, Lynn M.; Bird, Thomas D.; Yuan, Wuxing; Elman, Lauren; Clay, Dana; Wood, Elisabeth McCarty; Chen‐Plotkin, Alice S.; Martinez‐Lage, Maria; Steinbart, Ellen J.; McCluskey, Leo; Grossman, Murray; Neumann, Manuela; Wu, I‐Lin; Yang, Wei‐Shiung; Kalb, Robert G.; Galasko, Douglas; Montine, Thomas J.; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Schellenberg, Gerard D.; Yu, Chang‐En

doi:10.1016/s1474-4422(08)70071-1

Cited by 652 publications

(485 citation statements)

References 39 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: 89%

“…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: 76%

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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: 89%

Section: Introductionmentioning

confidence: 76%

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

et al. 2008

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“…It is well established that TDP-43 proteinopathies contribute to the pathological progression of motor-neuron diseases; [12][13][14][15][16][17] however, the interaction between virus infection and the host TDP-43 pathway has not yet been explored. In this study, we first examined the protein expression of TDP-43 in various models of CVB3 infection.…”

Section: Resultsmentioning

confidence: 99%

“…10,11 Previous studies have shown that mutations of TDP-43 are linked with neurodegenerative diseases, in particular, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). [12][13][14][15][16][17] In addition, aberrant cleavage and cytoplasmic aggregation of TDP-43 are identified as molecular signatures for most forms of ALS and FTLD and contribute significantly to disease progression. 18 However, the role of TDP-43 in virus-induced diseases has not been studied.…”

mentioning

confidence: 99%

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at aminoacid 327 between glutamine and alanine, resulting in the generation of an N-and C-terminal cleavage fragment of~35 and~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection. Coxsackievirus B3 (CVB3) is a small, positive-stranded RNA enterovirus. 1 The single open reading frame of CVB3 is translated into a viral polypeptide that is subsequently cleaved by two virus-encoded proteases 2A and 3C to generate structural and non-structural proteins. 2 In addition to processing viral polyprotein, 2A and 3C target host proteins important for maintenance of protein translation and transcription, antiviral activity, and cellular architecture and signaling, contributing to virus-induced pathogenesis. [3][4][5] Although enteroviral replication takes place exclusively in the cytoplasm, viral infection has been demonstrated to lead to cytoplasmic translocation of nuclear proteins. 6 For example, heterogeneous ribonucleoprotein D (hnRNP D) has been shown to translocate from the nucleus to the cytoplasm during enteroviral infection. 5,7,8 Moreover, hnRNP D is cleaved by 3C and has an antiviral function against enteroviral infection. 5,7,8 Cytoplasmic translocation after enteroviral infection has also been demonstrated for several other hnRNPs (A1, C, and K)...

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“…gesting that TDP-43 may be a causative protein for these disorders (1)(2)(3)(4)(5)(6). Here we first report the detailed clinical features of affected members of a Japanese family who suffered from ALS linked to TDP-43 M337V mutation.…”

Section: Amyotrophic Lateral Sclerosis (Als) Is a Progressive And Fatmentioning

confidence: 91%