Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ, Aziz M.; Vo, An; Árgyelán, Miklós; Tanabe, Lauren M.; Schiffer, Wynne K.; Dewey, Stephen L.; Dauer, William T.; Eidelberg, David

doi:10.1073/pnas.1016445108

Cited by 113 publications

(124 citation statements)

References 40 publications

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“…Similar to the imaging studies in patients, abnormal cerebellar function is observed in genetic mouse and rat models of dystonia (LeDoux and Lorden, 2002;Chen et al, 2009;Zhang et al, 2011). Indeed, an increase in metabolic activity in the cerebellum is observed in mouse models of DYT1 dystonia (Ulug et al, 2011;Zhao et al, 2011), similar to imaging studies in DYT1 patients. Furthermore, in normal mice, generalized dystonia is induced by delivery of the excitatory nonselective glutamate receptor agonist kainic acid to the midline cerebellum (Pizoli et al, 2002).…”

Section: Introductionsupporting

confidence: 70%

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Fan

Hughes²,

Jinnah³

et al. 2011

J Pharmacol Exp Ther

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Dystonia is a neurological disorder characterized by involuntary muscle contractions that cause twisting movements and abnormal postures. Functional imaging consistently reveals cerebellar overactivity in dystonic patients regardless of the type or etiology of the disorder. To explore mechanisms that might explain the basis for the cerebellar overactivity in dystonia, normal mice were challenged with intracerebellar application of a variety of agents that induce hyperexcitability. A nonspecific increase in cerebellar excitability, such as that produced by picrotoxin, was not associated with dystonia. Instead, glutamate receptor activation, specifically AMPA receptor activation, was necessary to evoke dystonia. AMPA receptor agonists induced dystonia, and AMPA receptor antagonists reduced the dystonia induced by glutamate receptor agonists. AMPA receptor antagonists also ameliorated the dystonia exhibited by the dystonic mouse mutant tottering, suggesting that AMPA receptors may play a role in some other genetic models of dystonia. Furthermore, AMPA receptor desensitization mediated the expression of dystonia. Preventing AMPA receptor desensitization with cyclothiazide or the nondesensitizing agonist kainic acid exacerbated the dystonic response. These results suggest the novel hypothesis that the cerebellar overactivity observed in neuroimaging studies of patients with dystonia may be an indirect reflection of abnormal glutamate signaling. In addition, these results imply that reducing AMPA receptor activation by blocking AMPA receptors and promoting AMPA receptor desensitization or negative allosteric modulators may prove to be beneficial for treating dystonia.

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Section: Introductionsupporting

confidence: 70%

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Fan

Hughes²,

Jinnah³

et al. 2011

J Pharmacol Exp Ther

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“…61,81 Studies in patients with clinically manifesting and non-manifesting DYT1 and DYT6 dystonia using diffusionbased tractography 82 showed reduced connectivity of the cerebellum with the thalamus, suggesting that disruption of cerebellar outflow could be an important factor affecting the occurrence of motor symptoms. A very similar pattern of changes in the cerebellar pathway was reported in DYT1 mutant mice with the torsin1A gene mutation, 83 although the relevance of this model to dystonia is debated. Whether these findings are specific to DYT1 and DYT6 dystonia or are also present in sporadic cases is unknown.…”

Section: Dystoniamentioning

confidence: 64%

Imaging insights into basal ganglia function, Parkinson's disease, and dystonia

Stoessl¹,

Lehericy²,

Strafella³

2014

The Lancet

141

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Recent advances in structural and functional imaging have greatly improved our ability to assess normal functions of the basal ganglia, diagnose parkinsonian syndromes, understand the pathophysiology of parkinsonism and other movement disorders, and detect and monitor disease progression. Radionuclide imaging is the best way to detect and monitor dopamine deficiency, and will probably continue to be the best biomarker for assessment of the effects of disease-modifying therapies. However, advances in magnetic resonance enable the separation of patients with Parkinson's disease from healthy controls, and show great promise for differentiation between Parkinson's disease and other akinetic-rigid syndromes. Radionuclide imaging is useful to show the dopaminergic basis for both motor and behavioural complications of Parkinson's disease and its treatment, and alterations in non-dopaminergic systems. Both PET and MRI can be used to study patterns of functional connectivity in the brain, which is disrupted in Parkinson's disease and in association with its complications, and in other basal-ganglia disorders such as dystonia, in which an anatomical substrate is not otherwise apparent. Functional imaging is increasingly used to assess underlying pathological processes such as neuroinflammation and abnormal protein Correspondence to: Prof A J Stoessl,

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“…Several mechanisms may underlie these patterns of vulnerability. The exclusive occurrence of molecular and neurodegenerative changes during the first several postnatal weeks suggests that processes highly active during CNS maturation may malities in dystonia (57), including in DYT1 dystonia (31). We sought but were unable to locate postmortem tissue of sufficient quantity or quality to carefully examine for the presence of neurodegeneration in DYT1 dystonia.…”

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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Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Cited by 113 publications

References 40 publications

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Imaging insights into basal ganglia function, Parkinson's disease, and dystonia

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

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