Generation and characterization of Dyt1 ΔGAG knock-in mouse as a model for early-onset dystonia

Dang, Mai T.; Yokoi, Fumiaki; McNaught, Kevin St. P.; Jengelley, Toni-Ann; Jackson, Tehone; Li, Jianyong; Li, Yuqing

doi:10.1016/j.expneurol.2005.08.025

Cited by 195 publications

(319 citation statements)

References 67 publications

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“…Increased latencies or slip counts in tests of beam walking, combined with normal Rotarod performance have also been documented in some studies (Dang et al, 2005(Dang et al, , 2006, while the reverse constellation of findings was seen in others (Grundmann et al, 2007). The published studies did not find abnormalities on footprint analyses (Dang et al, 2005;Grundmann et al, 2007), or vertical rope climbing (Dang et al, 2005(Dang et al, , 2006.…”

Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 83%

“…However, the available strains show abnormalities in behavioral tests. For instance, open field activity is increased in most of the published reports (Dang et al, 2005(Dang et al, , 2006Shashidharan et al, 2005;Grundmann et al, 2007). Increased latencies or slip counts in tests of beam walking, combined with normal Rotarod performance have also been documented in some studies (Dang et al, 2005(Dang et al, , 2006, while the reverse constellation of findings was seen in others (Grundmann et al, 2007).…”

Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 91%

“…A variety of genetically modified mouse strains have been described that either over-express human mutant torsinA (Sharma et al, 2005;Shashidharan et al, 2005;Grundmann et al, 2007), are heterozygous for mouse mutant torsinA (Dang et al, 2005), or in which expression of endogenous torsinA is reduced (Goodchild et al, 2005;Dang et al, 2006). The recent paper by Zhao et al in Experimental Neurology (Zhao et al, 2008) characterizes anatomical, behavioral and biochemical features of one of the strains that over-express mutant human torsinA, hMT1 mice, which were generated by Sharma et al (Sharma et al, 2005).…”

Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 99%

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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: 83%

Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 91%

Section: Animal Models For Dyt1 Dystoniamentioning

confidence: 99%

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Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

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“…Strikingly, one compound, ampicillin, was shown to restore functional capacity of torsinA to human DYT1 dystonia patient fibroblasts defective in protein processing. Administration of this drug also reversed behavioral abnormalities in a DYT1 knock-in mouse model of EOTD [54,75]. Although an antibiotic is not ideal for chronic dosing regimens in dystonia, the identification of a compound that selectively modifies torsinA activity across multiple cellular and organismal models represents a significant molecular lead toward novel treatment alternatives.…”

Section: Application Of C Elegans To Dystonia Researchmentioning

confidence: 99%

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

Dexter

Caldwell

2012

Neurotherapeutics

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Summary Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C.elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

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“…Conversely, rodents may be more capable of compensating, and therefore loss of the protein may manifest as a lesser dysfunction compared to humans. Because the present genetic dystonia rodent models that have been generated are knock-ins, knockouts, or transgenics; the disrupted gene is present from conception [48,[57][58][59]. Embryonic alterations in gene expression may be able to compensate for the loss of gene in mice, but not in humans.…”

Section: Rodent Models Of Dystoniamentioning

confidence: 99%