TorsinA protects against oxidative stress in COS-1 and PC12 cells

Kuner, Rohini; Teismann, Peter; Trutzel, Annette; Naim, Jomana; Richter, Angelika; Schmidt, Nicole; Ahsen, Oliver von; Bach, A.; Ferger, Boris; Schneider, Armin

doi:10.1016/s0304-3940(03)00904-2

Cited by 48 publications

(47 citation statements)

References 11 publications

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“…These data suggest that although wild-type torsins may slightly suppress the neurodegeneration associated with increased dopamine levels, this suppression is not statistically significant. This observed trend toward enhanced DA neuronal survival in the presence of torsin overexpression may reflect a more generalized role for protection from oxidative damage as reported previously in cell cultures exposed to hydrogen peroxide (Kuner et al, 2003;Shashidharan et al, 2004).…”

supporting

confidence: 81%

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

Cao¹,

Gelwix²,

Caldwell³

et al. 2005

J. Neurosci.

263

286

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Parkinson's disease (PD) is linked genetically to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Overexpression or mutation of ␣-synuclein results in the formation of Lewy bodies and neurodegeneration of dopaminergic (DA) neurons. Human torsinA, mutations in which cause another movement disorder termed early-onset torsion dystonia, is highly expressed in DA neurons and is also a component of Lewy bodies. Previous work has established torsins as having molecular chaperone activity. Thus, we examined the ability of torsinA to manage cellular stress within DA neurons of the nematode Caenorhabditis elegans. Worm DA neurons undergo a reproducible pattern of neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), a neurotoxin commonly used to model PD. Overexpression of torsins in C. elegans DA neurons results in dramatic suppression of neurodegeneration after 6-OHDA treatment. In contrast, expression of either dystonia-associated mutant torsinA or combined overexpression of wild-type and mutant torsinA yielded greatly diminished neuroprotection against 6-OHDA. We further demonstrated that torsins seem to protect DA neurons from 6-OHDA through downregulating protein levels of the dopamine transporter (DAT-1) in vivo. Additionally, we determined that torsins protect robustly against DA neurodegeneration caused by overexpression of ␣-synuclein. Using mutant nematodes lacking DAT-1 function, we also showed that torsin neuroprotection from ␣-synuclein-induced degeneration occurs in a manner independent of this transporter. Together, these data have mechanistic implications for movement disorders, because our results demonstrate that torsin proteins have the capacity to manage sources of cellular stress within DA neurons.

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supporting

confidence: 81%

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

Cao¹,

Gelwix²,

Caldwell³

et al. 2005

J. Neurosci.

263

286

View full text Add to dashboard Cite

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“…Unlike ClpA and ClpB, torsinA lacks a substrate-binding domain or other functional region outside its ATPase domain (11). Experimental evidence suggests that torsinA mediates varied cellular activities, including protection from toxic cellular stress (12)(13)(14)(15), trafficking of membrane-associated proteins (16), and synaptic vesicle recycling (17). In this regard, torsinA regulates trafficking of a G-protein-coupled receptor, dopamine transporters, and ion channels (16).…”

mentioning

confidence: 99%

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

Zhu

Millen

Mendoza

et al. 2010

Journal of Biological Chemistry

113

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Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (⌬E302/303) near the C terminus of torsinA, a member of the AAA؉ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ⌬E, are not currently understood. By contrast to other AAA؉ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ⌬E, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox-and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteinecontaining sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.Torsion dystonia is an autosomal dominant movement disorder that causes the muscles to contract and spasm involuntarily. These muscle contractions force the body into repetitive movements and often twisted postures. The most common and severe early onset form of dystonia has been linked to the mutations in the human DYT1 (TOR1A) gene encoding the protein torsinA (1, 2). Although the function of torsinA and the mechanism underlying dystonia disease remain obscure, the sequence of torsinA is homologous to a large and diverse group of ATP-dependent oligomeric proteins named the AAAϩ protein family. The AAAϩ proteins typically form oligomeric rings that catalyze a variety of cellular processes, including protein translocation, membrane trafficking, and conformational remodeling of regulatory factors (3-5). TorsinA is the founding member of a subfamily of AAAϩ proteins that includes torsinB (TOR1B) and two other related gene products (TOR2A and TOR3A) in mammals and OOC-5 in Caenorhabditis elegans (1, 6, 7).The signal sequence and the following hydrophobic region at the N terminus (Fig. 1A) target torsinA to the lumen of the endoplasmic reticulum (ER). 3 In the ER, torsinA perhaps acts on secreted (8, 9) or stress-related protein substrates (10). Unlike ClpA and ClpB, torsinA lacks a substrate-binding domain or other functional region outside its ATPase domain (11). Experimental evidence suggests that torsinA mediates varied cellular activities, including protection from toxic cellular stress (12-15), trafficking of membrane-associated proteins (16), and synaptic vesicle recycling (17). In this regard, torsinA regulates trafficking of a G-protein-coupled recept...

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“…DYT1 codes for torsinA protein, and the ΔGAG deletion removes a glutamic acid (ΔE) from the protein. The role of mutant torsinA in the development of dystonia is unknown, but possible functions of normal torsinA were reported to include its involvement in cytoskeletal dynamics, nuclear membrane formation, and neuroprotection (Kuner et al, 2003;Bragg et al, 2004;Gonzalez-Alegre & Paulson, 2004;Goodchild & Dauer, 2004;Shashidharan et al, 2004;Hewett et al, 2006;Kock et al, 2006). Also unknown is the nature of the genetic mutation in torsinA, an important aspect of the pathophysiology of dystonia that may affect the development of genetic-based therapeutics.…”

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confidence: 99%

Motor deficits and hyperactivity in Dyt1 knockdown mice

Dang

Yokoi²,

Pence³

et al. 2006

Neuroscience Research

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The DYT1 gene containing a trinucleotide deletion (ΔGAG) is linked to early-onset dystonia, a neurological movement disorder of involuntary muscle contractions. To understand Dyt1's contribution to dystonia, we produced and analyzed Dyt1 knockdown (KD) mice that expressed a reduced level of torsinA protein encoded by Dyt1. Knockdown mice exhibited deficits in motor control and a decreased trend in dopamine with a significant reduction in 3,4-dihydroxyphenylacetic acid. These alterations are similar to those displayed by previously reported Dyt1 ΔGAG knockin heterozygous mice, suggesting that the partial loss of torsinA function contributes to the pathology of the disease. KeywordsDyt1; torsinA; dystonia; knockdown; Tor1A; Dyt1 ΔGAG A trinucleotide deletion (ΔGAG) in the DYT1 gene is found in a majority of patients with Oppenheim's early-onset dystonia, a neurological disorder of uncontrollable muscle contractions (Ozelius et al., 1997). DYT1 codes for torsinA protein, and the ΔGAG deletion removes a glutamic acid (ΔE) from the protein. The role of mutant torsinA in the development of dystonia is unknown, but possible functions of normal torsinA were reported to include its involvement in cytoskeletal dynamics, nuclear membrane formation, and neuroprotection (Kuner et al., 2003;Bragg et al., 2004;Gonzalez-Alegre & Paulson, 2004;Goodchild & Dauer, 2004;Shashidharan et al., 2004;Hewett et al., 2006;Kock et al., 2006). Also unknown is the nature of the genetic mutation in torsinA, an important aspect of the pathophysiology of dystonia that may affect the development of genetic-based therapeutics.The ΔGAG mutation of DYT1 has been speculated to work through a toxic-gain-of-function mechanism by reports of protein aggregates caused by an overexpression of mutant torsinA in cultured cells and Drosophila (Hewett et al., 2000;Kustedjo et al., 2000;Koh et al., 2004). Also, in patient tissues and two mouse models, an overexpression transgenic and our Dyt1 ΔGAG knockin (Dyt1 ΔGAG) mouse lines, aggregates containing torsinA and ubiquitin were found primarily in the brainstem, even though torsinA is widely expressed throughout the brain Dang et al., 2005;Shashidharan et al., 2005). In contrast, other published findings have suggested that ΔGAG causes a loss of normal protein function (Torres et al., 2004;Goodchild et al., 2005). For example, nuclear envelope abnormalities were noted * To whom correspondence and proofs should be addressed. Yuqing Li, 3347 Beckman Institute, 405 N. Mathews Ave., Urbana, Illinois, 61801, Tel.:217-333-4002, Fax: 217-244-1726, E-mail: y-li4@uiuc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all l...

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TorsinA protects against oxidative stress in COS-1 and PC12 cells

Cited by 48 publications

References 11 publications

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

Motor deficits and hyperactivity in Dyt1 knockdown mice

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