Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias

Gill, Jason S.; Nguyen, Megan X.; Hull, Mariam; van der Heijden, Meike E.; Nguyen, Ken; Thomas, Sruthi P.; Sillitoe, Roy V.

doi:10.3389/dyst.2023.11805

Cited by 5 publications

(1 citation statement)

References 163 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GPi DBS, which is the most common target, has shown similar efficacy with both high (130Hz) and low (<60Hz) frequency DBS [4,21]. However basal ganglia targeting consistently shows decreased efficacy for acquired and heredodegenerative etiologies of the condition [29,52], increasing the urgency to develop new, effective targets.…”

Section: Dbs Of the Centrolateral Thalamic Nucleus But Not The Dorsal...mentioning

confidence: 99%

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

Nguyen,

Brown,

Lin

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a dystonia network consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical areas in the network - the basal ganglia, thalamus, and cerebellum - lead to a dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts instigates dystonia; and how network modulation interacts with symptom latency remain as unexplored questions. Here, we present an electrolytic lesioning paradigm that bilaterally targets the cerebellar outflow tracts. We found that lesioning these tracts, at the junction of the superior cerebellar peduncles and the medial and intermediate cerebellar nuclei, resulted in acute, severe dystonia. We observed that dystonia is reduced with one hour of DBS of the centrolateral thalamic nucleus, a first order node in the network downstream of the cerebellar nuclei. In contrast, one hour of stimulation at a second order node in the short latency, disynaptic projection from the cerebellar nuclei, the striatum, did not modulate the dystonia in the short-term. Our study introduces a robust paradigm for inducing acute, severe dystonia, and demonstrates that targeted modulation based on network principles powerfully rescues motor behavior. These data inspire the identification of therapeutic targets for difficult to manage acquired dystonia.

show abstract

Section: Dbs Of the Centrolateral Thalamic Nucleus But Not The Dorsal...mentioning

confidence: 99%

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

Nguyen,

Brown,

Lin

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

A frameshift mutation in the murinePrkragene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation

Burnett,

Culver,

Simon

et al. 2024

Preprint

View full text Add to dashboard Cite

Mutations inPrkragene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation,Prkralear-5Jexhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of thePrkralear-5Jmutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygousPrkralear-5Jmice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.Summary StatementThis study shows, for the first time, a role of reduced eIF2α phosphorylation in DYT-PRKRA and the cerebellum development in a mouse model.

show abstract

Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA

Burnett,

Culver,

Simon

et al. 2024

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkralear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.

show abstract

Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias

Cited by 5 publications

References 163 publications

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

A frameshift mutation in the murinePrkragene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation

Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA

Contact Info

Product

Resources

About