P3‐287: TDP‐43 A315T mutation in familial motor neuron disease

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

doi:10.1016/j.jalz.2008.05.1855

Cited by 160 publications

(235 citation statements)

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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.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2015

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“…This could be due to reduced penetrance of p.G357R, which is in agreement with other reported TARDBP mutations. [8][9][10][11][12]18 …”

Section: Discussionmentioning

confidence: 99%

“…This is within the range of what has been estimated in other ALS populations, 1-3%. [8][9][10][11][16][17][18][19] However, the ALS patients in our study were intentionally selected for a positive family history suggesting that mutations in TARDBP are rare in the Nordic ALS population.…”

Section: Novel Tardbp Mutations H-h Chiang Et Almentioning

confidence: 99%

“…6,7 Shortly after, studies found mutations segregating with disease, and functional studies supported a role for TDP-43 in motor neuron death. [8][9][10][11] To date, 45 TARDBP mutations have been reported in ALS patients (http://alsod.iop.kcl.ac.uk, http://bioinfo.hr/ pro-mine/), the majority located in the glycine-rich region of exon 6. Furthermore, although rare, mutations in TARDBP have also been detected in patients with FTD-ALS and FTD.…”

Section: Introductionmentioning

confidence: 99%

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