These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1dystonia and persists along development, representing a susceptibility factor for symptom generation.
The DeltaGAG deletion mutation in DYT1, causing a loss of a glutamic acid near the carboxyl terminus of torsinA protein (torsinADeltaE), is dominantly inherited and tends to result in a severe generalized form of dystonia with childhood onset.
DYT1dystonia is caused by an autosomal dominant mutation that leads to a glutamic acid deletion in torsinA (TA), a member of the AAA+ ATPase superfamily.
This review will summarize our current knowledge on the molecular and basic biological features of torsinA and its dysfunction when carrying disease-causing mutation, identifying future research priorities and proposing a model of dystonia pathogenesis that might extend beyond DYT1.
The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network.
In mice with the DYT1dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons.
To analyze contribution of rs3842225 and rs1182 single nucleotide polymorphisms (SNP) in TOR1A gene, the causative gene for the DYT1 form of hereditary early-onset generalized dystonia, to the development of focal and segmental dystonia in Russian patients.
DYT1dystonia is a neurological disease caused by a dominant mutation that results in the loss of a glutamic acid in the endoplasmic reticulum-resident protein torsinA.
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 DYT1dystonia.
The DYT1dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum.
Rodent models of DYT1dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses.
Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a.
The DYT1 mutation was also detected in 2 patients with multifocal dystonia, 1 of them presenting with involvement of cranial and cervical muscles, and in 2 patients with writer's cramp of both hands with only slight progression.
Evidence suggests that TOR1A mutation produces dystonia through an aberrant neuronal signalling within the striatum, where D2 dopamine receptors (D2R) produce an abnormal excitatory response in cholinergic interneurons (ChIs) in different models of DYT1 dystonia.
A dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A-related dystonia.
Abnormal processing, transport, or entrapment of VMAT2 within the mutant torsinA membranous inclusions, therefore, may affect cellular dopamine release, providing a potential pathogenic mechanism for the DYT1-dependent dystonia.