Structural insights into TDP-43 in nucleic-acid binding and domain interactions

Kuo, Pan Hsien; Doudeva, L.G.; Wang, Yi Ting; Shen, Che Kun James; Yuan, Hanna S.

doi:10.1093/nar/gkp013

Cited by 279 publications

(307 citation statements)

References 33 publications

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“…These data, consistent with those from co-immunoprecipitation (Fig. 2b), demonstrate that RRM1 is indispensable for TDP-43 or TDP-35 binding with nucleic acids, while RRM2 is also contributable to the binding by cooperatively enhancing the binding affinity of RRM12 [30]. …”

Section: Rrm1 Plays a Dominant Role In Nucleic-acid Bindingsupporting

confidence: 89%

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TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

Xia

Jiang

et al. 2015

FEBS Letters

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Edited by Barry HalliwellKeywords: TAR DNA binding protein of 43kDa C-terminal fragment of $35kDa Sequestration Cytoplasmic inclusion RNA recognition motif a b s t r a c t TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.

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Section: Rrm1 Plays a Dominant Role In Nucleic-acid Bindingsupporting

confidence: 89%

“…TDP-43 contains two RRM domains that can bind RNA as well as DNA [30]. So ssDNA can be applied to study the nucleic-acid binding abilities of the RRM domains in vitro, and thus the data may reflect the RNA binding properties of TDP-43 in cell.…”

Section: Rrm1 Plays a Dominant Role In Nucleic-acid Bindingmentioning

confidence: 99%

TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

Xia

Jiang

et al. 2015

FEBS Letters

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“…DISCUSSION TDP-43 has two highly conserved RNA recognition motifs flanked by the N-terminal and the C-terminal tail. 26 The most common underlying biochemical mechanism of TDP-43 cleavage is caspase-dependent producing 35 and 25 kDa fragments have been identified. 7,27 In a recent report, six calpain cleavages of TDP- 43 have also been putatively reported by Yamashita T, et al 12 In the present work, we compared TDP-43 fragments generated by caspase-3 and calpain TDP-43 cleavages ( Figure 3).…”

Section: Activated Calpain Cleaves Tdp-43 In Severe Traumatic Brain Imentioning

confidence: 99%

Dual Vulnerability of TDP-43 to Calpain and Caspase-3 Proteolysis after Neurotoxic Conditions and Traumatic Brain Injury

Yang

Lin

Robertson

et al. 2014

J Cereb Blood Flow Metab

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Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cortex in two TBI models: controlled cortical impact injury and overpressure blast-wave-induced brain injury. Finally, TDP-43 and its 35 kDa fragment levels were also elevated in the cerebrospinal fluid (CSF) of severe TBI patients. This is the first evidence that TDP-43 might be involved in acute neuroinjury and TBI pathology, and that TDP-43 and its fragments may have biomarker utilities in TBI patients.

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“…TDP-43 has multiple functions in gene transcription and translations 3,16 . RRMs of TDP-43 bind to both single-and double-stranded TG-DNAs and UG-rich RNA 17 , and HIV trans-activation response element (TAR) DNA 18 . TDP-43 dimerization has been shown by sizeexclusion chromatography (SEC) of the green fluorescent protein-tagged protein and from an examination of the structure of mouse RRM2 in complex with a single-stranded RNA 17 .…”

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confidence: 99%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-b to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

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Structural insights into TDP-43 in nucleic-acid binding and domain interactions

Cited by 279 publications

References 33 publications

TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

TDP‐35 sequesters TDP‐43 into cytoplasmic inclusions through binding with RNA

Dual Vulnerability of TDP-43 to Calpain and Caspase-3 Proteolysis after Neurotoxic Conditions and Traumatic Brain Injury

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

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