TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Arai, Tetsuaki; Hasegawa, Masato; Akiyama, Haruhiko; Ikeda, Kenji; Nonaka, Takashi; Mori, Hiroshi; Mann, David; Tsuchiya, Kuniaki; Yoshida, Mari; Hashizume, Yoshio; Oda, Tatsuro

doi:10.1016/j.bbrc.2006.10.093

Cited by 2,354 publications

(2,271 citation statements)

References 51 publications

Supporting

Mentioning

2,203

Contrasting

Unclassified

Order By: Relevance

“…It was previously reported that, under disease condition, the solubility of TDP-43 is changed and altered solubility is correlated with cytoplasmic translocation and aggregation of TDP-43 and disease progression. 17,31,32 To determine whether CVB3 infection affects TDP-43 solubility, cells were infected with CVB3 for 7 h and cellular proteins were extracted sequentially using RIPA and then urea buffers. We found that, in sham-infected cells, TDP-43 was mainly present in RIPA-soluble fraction, whereas in CVB3-infected cells, both native and cleavage forms of TDP-43 were transferred to the RIPA-insoluble, urea-soluble fraction ( Figure 5), suggesting that the solubility of TDP-43 is decreased after CVB3 infection.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to reduced solubility, a number of studies have shown that mutated TDP-43 and caspasederived C-terminal TDP-43 fragments that are often detected in the brain of ALS and FTLD patients are highly prone to aggregation. 17,22,31,32 Furthermore, it was reported that wildtype TDP-43 and cytoplasmically restricted TDP-43 (mutated at its NLS) are also able to form protein aggregates in the cytoplasm, which are associated with increased protein phosphorylation and ubiquitination, and co-localized with SG markers. 29,40 The exact mechanism leading to decreased solubility and increased aggregation of TDP-43 following CVB3 infection is still not known, but could be related to cytoplasmic translocation of TDP-43, which allows for direct interaction of the two RNA-recognition motifs (RRM 1 and 2) on full-length TDP-43 and TDP-43-N, with cytosolic SGs containing various RNA transcripts and proteins that are involved in protein ubiquitination and phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

View full text Add to dashboard Cite

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)...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The cause of ALS is largely unknown, but transactive response DNA-binding protein 43 (TDP-43), a nuclear protein involved in the regulation of RNA processing [1][2][3][4][5][6][7] , has recently attracted interest as a molecule relevant to the pathogenesis of this disease. TDP-43 is absent from the nucleus in which it normally resides but localizes in abnormal cytoplasmic inclusions in a considerable proportion of spinal cord motor neurons in the majority of sporadic ALS patients [8][9][10] . As TDP-43 is indispensable for embryonic development and neuronal cell survival in cell culture [2][3][4]7 and genetically modified animals 1 , abnormal localization of TDP-43 in ALS motor neurons is believed to have a pathogenic role in ALS.…”

mentioning

confidence: 99%

“…Various fragments have been identified in the brains and spinal cords of FTLD-TDP and ALS patients 3,4,[8][9][10]20 but the role of N-terminal fragments has not been attracted the attention of researchers. In this study, we show that calpain cleaves the C-terminal region of TDP-43 and generates multiple different fragments by sequentially cleaving the large N-terminal fragments.…”

mentioning

confidence: 99%

“…7c,d). The physiologically higher calpain activity in the ventral horns of the spinal cord may explain why mutations in the TARDBP gene cause ALS but not FTLD-TDP in affected patients [8][9][10]30,31 . Our studies of mutant TDP-43 imply that the same neuropathological changes may arise from different molecular mechanisms, that is, protease activation and increased vulnerability of the substrate to the protease.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

View full text Add to dashboard Cite

Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

show abstract

TDP-43 Proteinopathy in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Neumann¹,

Kwong²,

Sampathu³

et al. 2007

Arch Neurol

203

183

View full text Add to dashboard Cite

TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Cited by 2,354 publications

References 51 publications

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

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

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

TDP-43 Proteinopathy in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About