Generation of a novel rodent model for DYT1 dystonia

Grundmann, Kathrin; Glöckle, Nicola; Martella, Giuseppina; Sciamanna, Giuseppe; Hauser, Till; Yu, Libo; Castaneda, Salvador; Pichler, Bernd J.; Fehrenbacher, Birgit; Schaller, Martin; Nuscher, Brigitte; Haass, Christian; Hettich, Jasmin; Yue, Zhenyu; Nguyen, Huu Phuc; Pisani, Antonio; Rieß, Olaf; Ott, Thomas

doi:10.1016/j.nbd.2012.03.024

Cited by 70 publications

(83 citation statements)

References 48 publications

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“…In HD patients, DTI has also been shown to allow detection of altered tissue integrity in both preclinical and clinical stages of HD (Mascalchi et al, 2004;Reading et al, 2005;Rosas et al, 2006Rosas et al, , 2010Seppi et al, 2006;Bohanna et al, 2008;Klöppel et al, 2008;Douaud et al, 2009;Della Nave et al, 2010;Mandelli et al, 2010;Sritharan et al, 2010). DTI has also been successfully applied in an inducible rat model of HD (Van Camp et al, 2012) and in one of the transgenic rat models of HD (Antonsen et al, 2012;Blockx et al, 2012), as well as in other rodent disease models (Song et al, 2004;Boska et al, 2007;Lope-Piedrafita et al, 2008;Van Camp et al, 2009;Grundmann et al, 2012). DTI thus appears as a promising tool for monitoring neuropathology in transgenic SCA17 rats.…”

Section: Discussionmentioning

confidence: 99%

“…Rats, on the other hand, show excellent learning abilities compared to mice and are the species of choice for studying learning and memory in rodents and for pharmacological manipulations (Kujpers, 1999). Their larger brain size also facilitates direct invasive procedures and miniaturized physiological in vivo approaches such as structural and functional imaging of small brain structures (Casteels et al, 2011;Grundmann et al, 2012;Yu-Taeger et al, 2012), electrophysiology (Miller et al, 2010;Ortiz et al, 2012), or stem cell replacement (Rath et al, 2012;Ribeiro et al, 2012). The advantages of the rat prompted us to generate a transgenic rat model for SCA17, which, to our knowledge, is the first transgenic rat model for any inherited spinocerebellar ataxia.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Transgenic Rat Model for Spinocerebellar Ataxia Type 17 Recapitulates Neuropathological Changes and SuppliesIn VivoImaging Biomarkers

Kelp

Koeppen²,

Petrasch‐Parwez

et al. 2013

J. Neurosci.

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Spinocerebellar ataxia 17 (SCA17) is an autosomal-dominant, late-onset neurodegenerative disorder caused by an expanded polyglutamine (polyQ) repeat in the TATA-box-binding protein (TBP). To further investigate this devastating disease, we sought to create a first transgenic rat model for SCA17 that carries a full human cDNA fragment of the TBP gene with 64 CAA/CAG repeats (TBPQ64). In line with previous observations in mouse models for SCA17, TBPQ64 rats show a severe neurological phenotype including ataxia, impairment of postural reflexes, and hyperactivity in early stages followed by reduced activity, loss of body weight, and early death. Neuropathologically, the severe phenotype of SCA17 rats was associated with neuronal loss, particularly in the cerebellum. Degeneration of Purkinje, basket, and stellate cells, changes in the morphology of the dendrites, nuclear TBP-positive immunoreactivity, and axonal torpedos were readily found by light and electron microscopy. While some of these changes are well recapitulated in existing mouse models for SCA17, we provide evidence that some crucial characteristics of SCA17 are better mirrored in TBPQ64 rats. Thus, this SCA17 model represents a valuable tool to pursue experimentation and therapeutic approaches that may be difficult or impossible to perform with SCA17 transgenic mice. We show for the first time positron emission tomography (PET) and diffusion tensor imaging (DTI) data of a SCA animal model that replicate recent PET studies in human SCA17 patients. Our results also confirm that DTI are potentially useful correlates of neuropathological changes in TBPQ64 rats and raise hope that DTI imaging could provide a biomarker for SCA17 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Transgenic Rat Model for Spinocerebellar Ataxia Type 17 Recapitulates Neuropathological Changes and SuppliesIn VivoImaging Biomarkers

Kelp

Koeppen²,

Petrasch‐Parwez

et al. 2013

J. Neurosci.

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“…Overexpression of DYT1 mutant torsinA in mice causes modest abnormalities in measures of beam walking, pawprint analysis, and motor learning, but not abnormal movements similar to those in patients with DYT1 dystonia (22)(23)(24). DYT1 torsinA transgenic rats reportedly show hind limb clasping during tail suspension and abnormalities in the pawprint analysis (25). Mice heterozygous for DYT1 knockin (Tor1a +/ΔE ) or KO (Tor1a +/-) alleles also appear normal; reports differ as to whether these animals exhibit defects in a beam-walking task (26,27).…”

Section: Introductionmentioning

confidence: 86%

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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“…Notably, enhanced glutamatergic synaptic transmission has been demonstrated at cortico-striatal synapses in transgenic rodents overexpressing E-torsinA [13,20] and in E-torsinA knock-in mice [8]. Three forms of synaptic plasticity were affected:…”

Section: Discussionmentioning

confidence: 99%

“…(1) stimulus-induced increase in glutamatergic responses was greater than in wild-type controls (enhanced long-term potentiation) [20]; (2) the potentiated responses could not revert back to the non-potentiated level (lack of synaptic depotentiation) [13,20]; and (3) stimulus-induced suppression of glutamatergic responses was absent (lack of long-term depression) [8,13,20]. Although it was unclear whether these signal-enhancing effects were caused by pre-or postsynaptic dysfunction, these observations and those from the current study collectively indicate that glutamatergic synaptic transmission is dysregulated in the context of E-torsinA.…”

Section: Discussionmentioning

confidence: 99%

Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model

Iwabuchi

Kakazu

Koh

et al. 2013

Neuroscience Letters

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Generation of a novel rodent model for DYT1 dystonia

Cited by 70 publications

References 48 publications

A Novel Transgenic Rat Model for Spinocerebellar Ataxia Type 17 Recapitulates Neuropathological Changes and SuppliesIn VivoImaging Biomarkers

A Novel Transgenic Rat Model for Spinocerebellar Ataxia Type 17 Recapitulates Neuropathological Changes and SuppliesIn VivoImaging Biomarkers

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model

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