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.
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.
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.
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.
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.
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.
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.
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).
The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1dystonia are highlighted.
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.
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.
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.
Deep brain stimulation (DBS) has been used successfully to treat refractory dystonia, specifically globus pallidus interna (GPi) DBS for DYT1-positive PGD patients.
Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients.
This control mechanism is offset by a TorsinA mutation implicated in the severe movement disorder DYT1dystonia, suggesting a critical role for the functional Torsin-cofactor interplay <i>in vivo</i>.