Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells

Hewett, Jeffrey; Tannous, Bakhos A.; Niland, Brian; Nery, Flávia C.; Zeng, Juan; Li, Yu Qing; Breakefield, Xandra O.

doi:10.1073/pnas.0701185104

Cited by 132 publications

(142 citation statements)

References 77 publications

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“…Both of these experiments suggest that the nucleotide-binding state of torsinA is coupled to its redox status by its RRS. It is interesting to consider the possibility that the function of torsinA is regulated by redox and nucleotide status in the context of its proposed role as an ER chaperone (9,16) and putative involvement in the ER stress response (10). In addition, torsinA and LAP1 have six and three conserved cysteines, respectively; thus the formation of a disulfide-linked species of torsinA-LAP1/LULL1 could happen transiently and may be mediated by reduced glutathione inside cells under appropriate redox conditions.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…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).…”

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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“…TorA can have toxic effects on the function of the secretory pathway (Hewett et al, 2007), raising the possibility that a combination of the loss-of-function shown here and gain-offunction shown elsewhere might explain the dominant inheritance of DYT1 dystonia. The discovery that LULL1 regulates the distribution and activity of TorA within the ER and the NE paves the way for future exploration of how changes in its activity correlate with the development of disease.…”

Section: A B Vander Heyden Et Almentioning

confidence: 99%

LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by theDYT1Dystonia Mutation

Heyden

Naismith

Snapp

et al. 2009

MBoC

115

162

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TorsinA (TorA) is an AAA؉ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.

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“…Within neurons, wild-type torsinA localizes to the endoplasmic reticulum (Liu et al, 2003;Naismith et al, 2004;Hewett et al, 2007), while mutant torsinA protein is found in the perinuclear space (Hewett et al, 2000;Gonzalez-Alegre and Paulson, 2004;Goodchild and Dauer, 2004). Perhaps relevant to the topic of dopaminergic dysfunction to DYT1 dystonia, associations of mutant torsinA with the vesicular monoamine transporter (VMAT2) and with alphasynuclein have been described (Sharma et al, 2001;Misbahuddin et al, 2005).…”

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confidence: 99%

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

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A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary movements are disrupted by sustained muscle spasms and abnormal limb posturing. In a recent issue of Experimental Neurology, Zhao et al. (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.

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Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells

Cited by 132 publications

References 77 publications

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

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

LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by theDYT1Dystonia Mutation

Commentary: Dopaminergic dysfunction in DYT1 dystonia

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