TorsinA participates in endoplasmic reticulum-associated degradation

Nery, Flávia C.; Armata, Ioanna A.; Farley, Jonathan E.; Cho, JinAh; Yaqub, Uzma; Chen, Pan; Hora, Cintia Carla da; Wang, Qiuyan; Tagaya, Mitsuo; Klein, Christine; Tannous, Bakhos A.; Caldwell, Kim A.; Lencer, Wayne I.; Ye, Yihong; Breakefield, Xandra O.

doi:10.1038/ncomms1383

Cited by 107 publications

(146 citation statements)

References 61 publications

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“…These data were extended by a subsequent report showing that torsinA associates with components of the ER-associated degradation pathway, facilitating processing and selective degradation of improperly folded proteins, including the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein (Fig. 4d) [73].…”

Section: Application Of C Elegans To Dystonia Researchmentioning

confidence: 66%

“…(e) WT torsinA also reduces the ER stress response resulting from co-expression of mutant cystic fibrosis transmembrane conductance regulator (CFTR Δ508). Likewise, in a comparison of the ER stress response between DYT1 patient fibroblasts (WT/ΔE) and control fibroblasts (WT), the patient cells are more sensitive to ER stress [73]. (f) Human genetic studies have shown that individuals who carry the torsinA (ΔE) allele are far more likely to be nonmanifesting carriers if they also have a polymorphism at position 216 that is protective in trans (216H) and individuals with the D216 allele are far more likely to show the symptoms of DYT1 dystonia [74].…”

Section: Application Of C Elegans To Dystonia Researchmentioning

confidence: 99%

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A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

Dexter

Caldwell

2012

Neurotherapeutics

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Summary Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C.elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

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Section: Application Of C Elegans To Dystonia Researchmentioning

confidence: 66%

Section: Application Of C Elegans To Dystonia Researchmentioning

confidence: 99%

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

Dexter

Caldwell

2012

Neurotherapeutics

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“…The next newly-identified protein upregulated by TGF-β1 in HMEC-1 is torsin A: a member of the AAA+ ATPase superfamily located within the lumen of the nuclear envelope and endoplasmic reticulum, which interacts with transmembrane proteins [28]. Torsin A is associated with laminin-associated polypeptide 1 (LAP1), conventional kinesin light chain 1 (KLC1), vimentin and actin.…”

Section: Discussionmentioning

confidence: 99%

Differential Quantitative Proteomics of Human Microvascular Endothelial Cells 1 by iTRAQ Reveals Palladin to be a New Biomarker During TGF-?1 Induced Endothelial Mesenchymal Transition

Stasiak¹,

Gawryś²,

Popielarski³

et al. 2017

J Proteomics Bioinform

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The study uses global quantitative proteomics to investigate the molecular mechanisms behind the induction of endothelial-mesenchymal transition (EndMT) by transforming growth factor-β (TGF-β). Orbitrap Velos mass spectrometers and iTRAQ -a labeling-based analysis were used to perform a global and quantitative comparison of two proteomes of Human Microvascular Endothelial Cells-1 (HMEC-1) treated or not treated by TGF-β1. iTRAQ analysis identified 43 differentially-expressed proteins in the early stages of EndMT induced by TGF-β1. From 5522 identified proteins, 26 were downregulated and 17 were upregulated, including proteins such as palladin, POTE I, torsin A and nucleoporin (NDC1). Further analysis of palladin revealed its increased mRNA and protein expression in response to TGF-β and Snail transcription factor. Our findings demonstrate that the newly-identified proteins may be involved in early stages of biological processes leading to EndMT.

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“…Within the ER, several reports have pointed to a role for torsinA in protein trafficking or protein quality control. TorsinA is reported to participate in ER-associated protein degradation ("ERAD")-a process whereby misfolded ER proteins are exported from the ER space and degraded [66]. Studies in Caenorhabditis elegans [67] also point to a role in protein quality control pathways.…”

Section: Torsina Functionmentioning

confidence: 99%