Overexpression of torsinA in PC12 cells protects against toxicity

Shashidharan, P.; Paris, Nicolae; Sandu, Daniela; Karthikeyan, Laina; McNaught, Kevin St. P.; Walker, Ruth H.; Olanow, C. Warren

doi:10.1046/j.1471-4159.2003.02233.x

Cited by 47 publications

(39 citation statements)

References 40 publications

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“…A chaperone-like function has been recently suggested for torsinA (28)(29)(30). Consistently, our studies suggest that torsinA regulates the assembly͞disassembly process of polytopic membrane proteins.…”

Section: Discussionsupporting

confidence: 91%

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

Torres

Sweeney²,

Beaulieu³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

173

199

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Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. Here, we show that torsinA can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. The dystonia-associated torsinA deletion mutant (⌬E-torsinA) did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in ⌬E-torsinA reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of wild-type torsinA through a mechanism presumably involving association of wild-type and mutant torsinA. Taken together, our results provide evidence for a functional role for torsinA and a loss of function and a dominant-negative phenotype of the ⌬E-torsinA mutation. These properties may contribute to the autosomal dominant nature of the condition. deletion mutant ͉ cell surface ͉ endoplasmic reticulum ͉ transmembrane ͉ polytopic

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Section: Discussionsupporting

confidence: 91%

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

Torres

Sweeney²,

Beaulieu³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

173

199

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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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“…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.…”

mentioning

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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Overexpression of torsinA in PC12 cells protects against toxicity

Cited by 47 publications

References 40 publications

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

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

Motor deficits and hyperactivity in Dyt1 knockdown mice

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