These data introduce targets for future studies to identify which are causative and which are compensatory in DYT1dystonia, and thereby aid in defining appropriate therapies.
We also outline our experimental work in DYT1dystonia, a group of patients that share a genetically homogenous etiology and can be considered a prototypical dystonic disorder.
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.
In contrast, ʟ-DOPA, which is not usually effective for the treatment of DYT1dystonia, did not increase dopamine release in either Dyt1 or control mice.
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.
Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1.
These findings suggest distinct pathogenetic mechanisms between manif-DYT1 vs. non-manif-DYT1 and manif-non-DYT1 dystonia, especially in terms of possible nigral dopaminergic abnormalities.
Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months.
In the <i>Tor1a</i><sup>+/Δgag</sup> DYT1dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded.
The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1dystonia are highlighted.
There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance.
We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1dystonia (Tor1a<sup>+/Δgag</sup> mice, Tor1a<sup>+/-</sup> torsinA null mice, and their respective wild-types).
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.
We conclude that there is ample evidence to suggest that the cerebellum plays a role in some dystonias, including the early-onset primary torsion dystonia DYT1 and that further studies examining the role of this brain region and its interaction with the basal ganglia in dystonia are warranted.
Our study suggests that there is an association between rs35153737 and dystonia in a southwestern Chinese population, and it may be caused by high linkage disequilibrium between this deletion and potential pathogenic variants in TOR1A.