Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although basal ganglia dysfunction is implicated in many forms of dystonia, the underlying mechanisms are unclear. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented whereas proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated proteins identified in our screen are associated with pathogenic variants that cause inherited dystonic disorders in humans suggesting shared mechanisms across many different forms of dystonia.

Central Effects of Botulinum Neurotoxin—Evidence from Human Studies

For more than three decades, Botulinum neurotoxin (BoNT) has been used to treat a variety of clinical conditions such as spastic or dystonic disorders by inducing a temporary paralysis of the injected muscle as the desired clinical effect. BoNT is known to primarily act at the neuromuscular junction resulting in a biochemical denervation of the treated muscle. However, recent evidence suggests that BoNT’s pharmacological properties may not only be limited to local muscular denervation at the injection site but may also include additional central effects. In this review, we report and discuss the current evidence for BoNT’s central effects based on clinical observations, neurophysiological investigations and neuroimaging studies in humans. Collectively, these data strongly point to indirect mechanisms via changes to sensory afferents that may be primarily responsible for the marked plastic effects of BoNT on the central nervous system. Importantly, BoNT-related central effects and consecutive modulation and/or reorganization of the brain may not solely be considered “side-effects” but rather an additional therapeutic impact responsible for a number of clinical observations that cannot be explained by merely peripheral actions.

Tardive Dystonia: Clinical Spectrum and Novel Manifestations

Tardive dystonia was identified in 25 patients: involvement of the face and neck was most common; truncal and limb dystonia were also observed. There were 3 cases of laryngospasm and 2 of spasmodic dysphonia. The latter has not been previously reported as a manifestation of tardive dystonia. In all cases, movements typical of classic tardive dyskinesia could be demonstrated. This group illustrates the variety of dystonic disorders that may occur in conjunction with tardive dyskinesia.