TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice

doi:10.1016/j.neulet.2003.10.069

Neuroscience Letters

Volume 355, Issues 1–2, 23 January 2004, Pages 126-130

https://doi.org/10.1016/j.neulet.2003.10.069 Get rights and content

Abstract

Early-onset torsion dystonias are caused by a mutation in TorsinA, a protein widely expressed in the nervous system. Here we report the cloning of the murine TorsinA cDNA and a mRNA in situ hybridization analysis of the expression patterns of TorsinA over developmental periods relevant to the etiology of early-onset dystonias. Several studies have demonstrated a functional involvement of the nigrostriatal dopaminergic system in pathological mechanisms underlying dystonia. In this study, we show that the expression of TorsinA is significantly increased in the brain within hours of treatment with the dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, suggesting that the TorsinA gene is regulated by cellular stress. These results provide insights into the pathophysiology of early-onset dystonia and strengthen links between the dopaminergic system and dystonia.

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Cited by (25)

Principles and Practice of Movement Disorders
2021, Principles and Practice of Movement Disorders
Dystonia: Phenotypes and Genetics
2015, Movement Disorders: Genetics and Models: Second Edition
Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia-plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can also be present. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1, respectively. Although significant recent progress has been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.
Generation of a novel rodent model for DYT1 dystonia
2012, Neurobiology of Disease
Citation Excerpt :
The protein torsinA belongs to the AAA + (ATPase associated with different cellular activities) protein family. Studies in recent years have implicated torsinA in cellular response to stress (Hewett et al., 2003; Kuner et al., 2004), in neurite outgrowth (Ferrari-Toninelli et al., 2004; Hewett et al., 2006), synaptic plasticity (Martella et al., 2009) and dopaminergic transmission (Augood et al., 2002, 2003; Marsden et al., 1985; Torres et al., 2004). Despite the increasing knowledge about the normal function of the protein, the relationship between the impaired function of mutant torsinA protein and the development of DYT1 dystonia is still unclear.
A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (∆ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood.
Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology.
We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in ∆ETorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of ∆ETorA and to test for therapeutic approaches.
The Genetics of Dystonias
2012, Advances in Genetics
Citation Excerpt :
TorsinA facilitates clearance of another dystonia-related protein, ε-sarcoglycan, by the ubiquitin proteosome system (Esapa et al., 2007). TorsinA appears to protect PC12 cells against cellular insults, such as serum deprivation and oxidative stress (Esapa et al., 2007; Kuner et al., 2003; Shashidharan et al., 2004), and dopaminergic neurons from oxidative stress in mice (Kuner et al., 2004) and C. elegans (Cao et al., 2005). The chaperone functions of torsinA may be essential during developmental processes, which seemingly involve interaction with cytoskeletal elements (Ferrari-Toninelli et al., 2004; Hewett et al., 2006; Kamm et al., 2004).
Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can be present as well. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1. Mutations in THAP1 and CIZ1 have been associated with sporadic and familial adult-onset dystonia. Although significant recent progress had been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.
Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia
2010, Neurobiology of Disease
Citation Excerpt :
This is an interesting finding as evidence increases that torsinA has profound implication in the development of the nervous system. First, expression levels of torsinA are considerably higher during early postnatal development in different organisms (Kuner et al., 2004; Siegert et al., 2005; Xiao et al., 2004). Moreover, mice lacking torsinA and mice homozygous for the GAG mutation are not viable (Dang et al., 2005; Goodchild et al., 2005), suggesting that torsinA is indispensable during a certain phase of embryonic development although its precise role in the developing brain is still unclear.
DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ∼ 30–40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms.
In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.
We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.
Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.
Glial elements contribute to stress-induced torsinA expression in the CNS and peripheral nervous system
2008, Neuroscience
Citation Excerpt :
This parallels in many respects the acute post-ischemic induction of many ischemia-responsive genes including many heat shock proteins (Nowak, 1991; Kawagoe et al., 1992; Xue et al., 1998; Nowak and Kiessling, 1999; Yagita et al., 2001; Tanaka et al., 2002). Studies in other in vivo and in vitro models also suggest a role for torsinA in response to oxidative stress (Hewett et al., 2003; Kuner et al., 2004; Cao et al., 2005). In contrast, the delayed component of torsinA increase includes prominent expression in reactive astrocytes in regions of hippocampus (e.g. CA1) known to undergo neuron loss and synaptic reorganization after ischemia (Arabadzisz and Freund, 1999; Briones et al., 2004).
DYT1 dystonia is caused by a single GAG deletion in exon 5 of TOR1A, the gene encoding torsinA, a putative chaperone protein. In this study, central and peripheral nervous system perturbations (transient forebrain ischemia and sciatic nerve transection, respectively) were used to examine the systems biology of torsinA in rats. After forebrain ischemia, quantitative real-time reverse transcriptase-polymerase chain reaction identified increased torsinA transcript levels in hippocampus, cerebral cortex, thalamus, striatum, and cerebellum at 24 h and 7 days. Expression declined toward sham values by 14 days in striatum, thalamus and cortex, and by 21 days in cerebellum and hippocampus. TorsinA transcripts were localized to dentate granule cells and pyramidal neurons in control hippocampus and were moderately elevated in these cell populations at 24 h after ischemia, after which CA1 expression was reduced, consistent with the loss of this vulnerable neuronal population. Increased in situ hybridization signal in CA1 stratum radiatum, stratum lacunosum-moleculare, and stratum oriens at 7 days after ischemia was correlated with the detection of torsinA immunoreactivity in interneurons and reactive astrocytes at 7 and 14 days. Sciatic nerve transection increased torsinA transcript levels between 24 h and 7 days in both ipsilateral and contralateral dorsal root ganglia (DRG). However, increased torsinA immunoreactivity was localized to both ganglion cells and satellite cells in ipsilateral DRG but was restricted to satellite cells contralaterally. These results suggest that torsinA participates in the response of neural tissue to central and peripheral insults and its sustained up-regulation indicates that torsinA may contribute to remodeling of neuronal circuitry. The striking induction of torsinA in astrocytes and satellite cells points to the potential involvement of glial elements in the pathobiology of DYT1 dystonia.

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TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice

Abstract

Brain Res.

J. Biol. Chem.

Am. J. Pathol.

Brain Res.

Brain Res. Mol. Brain Res.

Dopamine transmission in DYT1 dystonia: a biochemical and autoradiographical study

Neurology

Distribution of the mRNAs encoding TorsinA and TorsinB in the normal adult human brain

Ann. Neurol.

Dystonia

Curr. Opin. Neurol.