Developmental patterns of torsinA and torsinB expression

Vasudevan, Anju; Breakefield, Xandra O.; Bhide, Pradeep G.

doi:10.1016/j.brainres.2005.12.087

Cited by 50 publications

(49 citation statements)

References 49 publications

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“…These data raise the possibility that relative levels of expression of torsinA and torsinB may determine the vulnerability of a neuron to torsinA hypofunction. Interestingly, the expression levels of torsinA and torsinB change considerably and inversely during postnatal development (42), suggesting that this mechanism may also contribute to the developmental-dependent aspect of torsinA loss of function.…”

Section: Discussionmentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA + ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a flox/-) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a flox/ΔE ) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a flox/ΔE compared with nestin-Cre Tor1a flox/-animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia. IntroductionThe primary dystonias, a group of sporadic and inherited illnesses, are a striking example of selective vulnerability of CNS sensorimotor circuits (1, 2). Dystonia -defined as prolonged, involuntary twisting movements -is traditionally classified as "primary" if it occurs in isolation and in the absence of neuropathological change. In contrast, "secondary" dystonic movements occur consequent to CNS damage (e.g., from stroke, trauma, or neurodegeneration), and are typically accompanied by additional neurological signs and symptoms. This classification scheme has been criticized (3), however, because neuroimaging of patients with primary dystonia indicates the presence of subtle neuropathological changes, and few primary dystonia brains have been comprehensively analyzed (4). Indeed, despite considerable interest in the pathophysiology of primary dystonia, the molecular and cellular underpinnings of CNS dysfunction and the identity of affected motor structures and cell types remain poorly understood. DYT1 dystonia is a common inherited form of primary dystonia that typically manifests during a discrete period of childhood, implicating abnormal development as the cause of motor dysfunction. This neurodevelopmental disease is caused by a 3 bp in-frame mutation in TOR1A that removes a single glutamic acid residue (ΔE) from the torsinA protein. TorsinA is a ubiquitously expressed AAA + protein residing in the lumen of the ER/nuclear envelope (ER/NE) space (5-7). Accumulating evidence indicates that the DYT1 mutation acts by impairing torsinA function through multiple mechan...

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Section: Discussionmentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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“…The expression of torsinA is developmentally regulated with the highest levels of transcript and protein seen during the prenatal and early postnatal periods (Xiao et al, 2004). The expression of torsinA is particularly intense in cerebellar cortex and striatal cholinergic interneurons at Postnatal Day 14, a period of intense dendritogenesis and synaptogenesis in these regions (Xiao et al, 2004;Vasudevan et al, 2006). A torsinA homologue, OOC-5, present in C. elegans, plays an essential role in Par protein localization.…”

Section: Nih Public Accessmentioning

confidence: 99%

Glial elements contribute to stress-induced torsinA expression in the CNS and peripheral nervous system

et al. 2008

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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. After forebrain ischemia, quantitative real-time RT-PCR identified increased torsinA transcript levels in hippocampus, cerebral cortex, thalamus, striatum, and cerebellum at 24 h and 7 d. Expression declined toward sham values by 14 d in striatum, thalamus and cortex, and by 21 d 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 d 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. KeywordsDYT1; dystonia; reactive astrocytes; hippocampus; satellite cells; dorsal root ganglia DYT1 dystonia obeys an autosomal dominant inheritance pattern with reduced penetrance, usually begins in childhood and frequently generalizes. The causal mutation is a GAG deletion in the TOR1A gene that removes a single glutamic acid residue near the carboxy terminus of the encoded protein torsinA (Ozelius et al., 1997;Ozelius et al., 1999 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 legal disclaimers that apply to the journal pertain. Neuwald et al., 1999;Kamm et al., 2004;Callan et al., 2007). Members of the AAA+ family function as molecular chaperones for protein quality control (protein complex assembly, operation, disassembly, protein folding, unfolding, and degrad...

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“…These findings suggest an imbalance in dopaminergic neurotransmission and lend credence to the idea of a functional disturbance in patients with DYT1 dystonia. Interestingly, in situ hybridization and immunocytochemical studies have revealed high-level torsinA protein expression within dopaminergic neurons of the substantia nigra pars compacta and cholinergic interneurons of the striatum Walker et al, 2001;Oberlin et al, 2004;Xiao et al, 2004;Vasudevan et al, 2006). Furthermore, torsinA has been shown to protect dopaminergic neurons from oxidative stress (Kuner et al, 2004;Cao et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Zhao

DeCuypere

LeDoux

2008

Experimental Neurology

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A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA-and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.

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Developmental patterns of torsinA and torsinB expression

Cited by 50 publications

References 49 publications

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

Glial elements contribute to stress-induced torsinA expression in the CNS and peripheral nervous system

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

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