Project description:Variants in the PRKRA gene, which encodes PACT, cause the early-onset primary dystonia DYT-PRKRA, a movement disorder associated with disruption of coordinated muscle movements. PACT and its murine homolog RAX activate protein kinase R (PKR; also known as EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of 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 investigated the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicated that the truncated PACT/RAX protein retains its ability to interact with PKR but inhibits PKR activation. Mice homozygous for the mutation showed abnormalities in cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation was noted in the cerebellum and Purkinje neurons of the homozygous Prkralear-5J mice. These findings 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 the Prkralear-5J mutation.

| S-EPMC11625895 | biostudies-literature

Childhood-Onset Generalized Dystonia Due to NDUFA9 Gene Mutation: An Expansion of Mutations Causing Leigh's Syndrome.

Project description: Not available

| S-EPMC10645225 | biostudies-literature

Luteolin protects DYT-PRKRA cells from apoptosis by suppressing PKR activation.

Project description:DYT-PRKRA is a movement disorder caused by mutations in the PRKRA gene, which encodes for PACT, the protein activator of interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase PKR. PACT brings about PKR's catalytic activation by a direct binding in response to stress signals and activated PKR phosphorylates the translation initiation factor eIF2α. Phosphorylation of eIF2α is the central regulatory event that is part of the integrated stress response (ISR), an evolutionarily conserved intracellular signaling network essential for adapting to environmental stresses to maintain healthy cells. A dysregulation of either the level or the duration of eIF2α phosphorylation in response to stress signals causes the normally pro-survival ISR to become pro-apoptotic. Our research has established that the PRKRA mutations reported to cause DYT-PRKRA lead to enhanced PACT-PKR interactions causing a dysregulation of ISR and an increased sensitivity to apoptosis. We have previously identified luteolin, a plant flavonoid, as an inhibitor of the PACT-PKR interaction using high-throughput screening of chemical libraries. Our results presented in this study indicate that luteolin is markedly effective in disrupting the pathological PACT-PKR interactions to protect DYT-PRKRA cells against apoptosis, thus suggesting a therapeutic option for using luteolin to treat DYT-PRKRA and possibly other diseases resulting from enhanced PACT-PKR interactions.

| S-EPMC9974672 | biostudies-literature

DYT-PRKRA Mutation P222L Enhances PACT's Stimulatory Activity on Type I Interferon Induction.

Project description:DYT-PRKRA (dystonia 16 or DYT-PRKRA) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a PKR activator protein during integrated stress response (ISR) is the best characterized. Previously, we have established that the DYT-PRKRA mutations cause enhanced activation of PKR during ISR to sensitize DYT-PRKRA cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT-PRKRA patients alters PACT's functional role in induction of type I IFNs via the retinoic acid-inducible gene I (RIG-I) signaling. Our results indicate that the P222L mutation augments PACT's ability to induce IFN β in response to dsRNA and the basal expression of IFN β and IFN-stimulated genes (ISGs) is higher in DYT-PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT-PRKRA cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT-PRKRA.

| S-EPMC9138762 | biostudies-literature

DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations.

Project description:ObjectiveTo report 4 novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization.MethodsWe screened 4 families including a total of 11 definitely affected members with a clinical picture resembling the original description.ResultsFour novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, and R121W. In silico modeling showed that all variants have characteristics similar to R2G. The variants segregate with the disease in 3 of the families with evidence of incomplete penetrance in 2 of them. All 4 variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The hobby horse gait was evident in only 1 patient in this case series.ConclusionsOur interpretation is that laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.

| S-EPMC8105968 | biostudies-literature

Gait Impairment in Myoclonus-Dystonia (DYT-SGCE).

Project description:Background:Myoclonus-dystonia usually presents variable combination of myoclonus and dystonia mainly affecting the neck and arms, but leg involvement, especially as the presenting sign, is not common. Case report:A 29-year-old lady with a heterozygous mutation in Epsilon-sarcoglycan (SGCE) gene is presented with rapid jerks of the right leg interfering with walking. She has also manifested dystonic posture and jerks of the trunk and proximal upper limbs. Discussion:Although it is not typical, leg involvement could be a manifestation of myoclonus-dystonia either at presentation or during disease progression.

| S-EPMC6691910 | biostudies-other

Naming Genes for Dystonia: DYT-z or Ditzy?

Project description:Dystonias are a clinically and etiologically diverse group of disorders. Numerous genes have now been associated with different dystonia syndromes, and multiple strategies have been proposed for how these genes should be lumped and split into meaningful categories. The traditional approach has been based on the Human Genome Organization's plan for naming genetic loci for all disorders. For dystonia this involves a DYT prefix followed by a number (e.g., DYT1, DYT2, DYT3, etc.). A more recently proposed approach involves assigning multiple prefixes according to the main elements of the phenotype (e.g., DYT, PARK, CHOR, TREM, etc.) followed by the name of the responsible gene. This article describes these nomenclature systems and summarizes some of their limitations. We focus on dystonia as an example, although the concepts may be applied to all movement disorders.

| S-EPMC6714488 | biostudies-other

Long-Term Efficacy of Pallidal Deep Brain Stimulation in a Patient with DYT-THAP1 (DYT-6) Dystonia from India.

Project description: Not available

| S-EPMC9175436 | biostudies-literature

Haloperidol in Managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response.

Project description: Not available

| S-EPMC11300396 | biostudies-literature