Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann, Thomas

doi:10.1016/j.expneurol.2008.04.020

Cited by 65 publications

(46 citation statements)

References 83 publications

(116 reference statements)

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“…Some forms of dystonia are clearly associated with basal ganglia dysfunction. For instance, dystonia may result from disturbances in dopaminergic transmission assumed to affect strongly basal ganglia activity [183]. Thus, dystonia may develop either acutely or delayed (tardive dystonia), in normal individuals treated with dopamine-receptor blocking agents, or can be a sign of other diseases with disturbed dopamine metabolism, such as PD, levodopa-responsive dystonia, or DYT1 [184][185][186][187][188][189].…”

Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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Deep brain stimulation (DBS) is highly effective for both hypo-and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal gangliathalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

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Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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“…We speculate that in mut-Tg mice, neurons are more vulnerable to elevated calcium levels and thus develop hyperexcitability when challenged with coffee, alcohol, or stress. In our mutant PNKD mouse model and other generalized dystonia mouse models, dysregulated dopamine signaling has been demonstrated in the striatum (10,(33)(34)(35)(36)(37).…”

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confidence: 90%

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Shen¹,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.paroxysmal dyskinesia | exocytosis | neurological disease P aroxysmal nonkinesigenic dyskinesia (PNKD)* is a rare dominantly inherited episodic movement disorder. First reported in 1940 (1), PNKD is characterized by childhood onset with involuntary movements in the limbs, trunk, and face manifesting as dystonia, chorea, and athetosis (2). PNKD shows nearly complete penetrance and attacks are precipitated by fatigue, stress, hunger, and consumption of coffee or alcohol. Patients are completely normal between attacks.Hereditary forms of many episodic disorders are recognized and include movement disorders, muscle diseases, cardiac arrhythmias, epilepsy, and headache. A majority of the causative genes that have been identified encode ion channels (3). Studies in several spontaneous mouse mutants with a paroxysmal dyskinesia phenotype have provided intriguing insights into these otherwise complicated diseases (4-6). The tottering and lethargic mice display motor abnormalities mimicking paroxysmal dyskinesia and harbor mutations in the genes encoding the α1A and β4 subunits of the P/Q-type voltage-gated Ca 2+ -channel, respectively (7,8). Like PNKD, the dyskinesia phenotype in tottering mice can also be triggered by caffeine and stress. PNKD is interesting in that the gene encodes a novel protein with homology to human glyoxalase II, an enzyme in a stress-response pathway. Although the normal role of PNKD is unknown, we previously identified the causative gene of PNKD (9) and a mouse model of the human mutations recapitulates the phenotype and shows dopamine signaling dysregulation (10).At synapses, vesicle priming, docking, and fusion at synaptic terminals are complex and coordinately regulated by proteins from the active zone, presynaptic membrane, and vesicles (11). Rab3-interacting molecules (RIMs) are a family of active zone proteins encoded by genes, Rims 1 to 4 (12). Through their interactions with vesicle proteins, active zone proteins, and presynaptic membrane proteins, RIMs are centrally involved in basic parameters of neurotransmitter release, and they contribute to both long-term and short-term synaptic plasticity (13-18).Given that PNKD is a novel protein whose function is unknown, we set out to identify ...

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“…Multiple lines of evidence suggest a role for abnormalities of the DA system in the pathophysiology of dystonia (reviewed in Wichmann, 2008). Previous studies in torsinA transgenic and knockdown mice have shown alterations in striatal levels of DA and/or its metabolites (Dang et al 2005, 2006; Grundmann et al, 2007; Zhao et al 2008); however, as both increases and decreases have been reported, the question of how the DA system is affected remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

Page

André

et al. 2010

Neurobiology of Disease

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Early onset torsion dystonia is an autosomal dominant movement disorder of variable caused by a glutamic acid, i.e. ΔE, deletion in DYT1, encoding the protein torsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (ΔE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-ΔE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies.

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Commentary: Dopaminergic dysfunction in DYT1 dystonia

Cited by 65 publications

References 83 publications

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

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