Primary dystonia: molecules and mechanisms

Tanabe, Lauren M.; Kim, Connie E.; Alagem, Noga; Dauer, William T.

doi:10.1038/nrneurol.2009.160

Cited by 145 publications

(134 citation statements)

References 109 publications

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“…Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2).…”

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confidence: 99%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

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

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The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

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confidence: 99%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

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

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113

112

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“…In humans, the dystonia-specific Torsin1A (TOR1A) mutation TOR1A DE302/303 (also known as TOR1A DGAG ; referred to as Torsin DE in this paper) at the DYT1 gene locus is linked to early-onset primary dystonia (Tanabe et al, 2009). Mouse models expressing TOR1A DE302/303 accumulate abnormal vesicular structures at the NE (Goodchild et al, 2005;Naismith et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

A Novel Locomotion-based Validation Assay for Candidate Drugs Using Drosophila DYT1 Disease Model

Ito¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERMassachusetts General Hospital Charlestown, Massachusetts 02129 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe have established fly lines expressing a mutant form of human torsinA (torsinAΔE) in fly brains. We have shown that (1) human torsinAΔE protein is expressed in fly brains; (2) expression of human torsinAΔE dominantly suppresses larval locomotion and GTPC cyclrohydolase protein levels; (3) supplementation of dopamine can partially rescue the locomotion defects of Drosophila larvae caused by the expression of human torsinAΔE. These results demonstrated that human torsinA can cause locomotion defects and reduction of GTP cyclohydrolase proteins very similar to the phenotypes in dtorsin-null larval brains. These results suggested that we can study the molecular defects of human torsinAΔE using our fly model system. We have submitted a manuscript describing our results. We have conducted preliminary RNAi screen to identify modifiers of dtorsin-null locomotion defect phenotype. Our preliminary results suggest that (1) dopamine signaling pathway; (2) RNP transport pathway; (3) axon guidance pathway; and (4) other early-onset dystonia genes as candidates for modifiers. These RNAi screen will be very useful for identifying potential therapeutic targets of early-onset dystonia patients.

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“…Despite the shortcomings of the current genetic models of dystonia, they have in some cases demonstrated that loss or mutation of a particular dystonia gene can alter the function of neurons and connectivity of brain regions [29,44,50,[60][61][62][63]. Whether or not these dysfunctions are compensatory or causal in nature remains to be established.…”

Section: Rodent Models Of Dystoniamentioning

confidence: 99%