TorsinA immunoreactivity in brains of patients with
            <i>DYT1</i>
            and non-
            <i>DYT1</i>
            dystonia

Walker, Ruth H.; Brin, Mitchell F.; Sandu, Daniela; Good, Paul F.; Shashidharan, P.

doi:10.1212/wnl.58.1.120

Cited by 74 publications

(68 citation statements)

References 9 publications

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“…The question of whether inclusion body pathology is specific to the transgenic mouse models, or whether it is also part of human DYT1 disease remains somewhat controversial. Most histopathological studies of brains from patients with DYT1 failed to find evidence of protein accumulation or inclusion bodies (Walker et al, 2002;Rostasy et al, 2003), but a recent study of postmortem material from DYT1 patients has reported that perinuclear inclusion bodies are present in neurons in various brain stem areas (McNaught et al, 2004).…”

Section: Animal Models For Dyt1 Dystoniamentioning

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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Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 99%

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

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“…Postmortem analysis of DYT1 brain has not identified specific neuropathological findings or changes in TA expression or subcellular distribution (Augood et al, 2002;Walker et al, 2002;Rostasy et al, 2003). Studies in cell-based models of DYT1, however, have revealed aberrant localization of mutant TA (TAmut).…”

Section: Introductionmentioning

confidence: 99%

Aberrant Cellular Behavior of Mutant TorsinA Implicates Nuclear Envelope Dysfunction in DYT1 Dystonia

Gonzalez‐Alegre¹,

Paulson²

2004

J. Neurosci.

152

140

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Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia, is caused by a three base pair deletion that eliminates a single amino acid from the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in the endoplasmic reticulum (ER), yet both its cellular function and the basis for neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is the fact that mutant, but not wild-type, torsinA forms membranous inclusions in cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA. Although in this model torsinA displays some properties consistent with ER localization, mutant torsinA also accumulates in the nuclear envelope (NE), a structure contiguous with cytoplasmic ER. Consistent with this, membranous inclusions formed by mutant torsinA are shown to derive not from the ER, as thought previously, but from the NE. We demonstrate further that torsinA forms different disulfide-linked complexes that may be linked functionally to subcellular localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in NE structures, nucleocytoplasmic transport of a reporter protein was unaffected. These findings, togetherwithparallelstudiesfailingtodemonstrateperturbationofERfunction,implicatetheNEasaprimarysiteofdysfunctioninDYT1.DYT1 dystonia can be added to the growing list of inherited neurological disorders involving the NE.

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“…In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the cytoplasm, neuronal processes, and synaptic terminals (2,3,15,(23)(24)(25)(26) and has been shown to bind cytosolic proteins snapin (27) and kinesin light chain 1 (20). TorsinA has been proposed to play a role in several cellular processes, including dopaminergic neurotransmission (28 -31), NE organization and dynamics (17,22,32), and protein trafficking (27,33).…”

mentioning

confidence: 86%

“…This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2,3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4).…”

mentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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TorsinA immunoreactivity in brains of patients with DYT1 and non- DYT1 dystonia

Cited by 74 publications

References 9 publications

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Aberrant Cellular Behavior of Mutant TorsinA Implicates Nuclear Envelope Dysfunction in DYT1 Dystonia

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

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