Human movement disorders, including Parkinson’s disease (PD) and dystonia, represent a substantial societal burden afflicting millions of people worldwide. Therapeutic options for these diseases are generally limited to treating symptoms rather than targeting the underlying molecular mechanisms. Early-onset torsion dystonia (EOTD) is characterized by involuntary muscle contractions and abnormal postures, which occur as a consequence of neuronal dysfunction. Mutation of the DYT1 gene, encoding human torsinA, results in this dominantly inherited disorder. TorsinA is an ATPase that is thought to function like a chaperone in normal cells. EOTD is non-degenerative, as the affected neurons in the brains of patients remain intact. Furthermore, this disorder displays reduced penetrance, whereby only 30-40% of carriers exhibit symptoms. These combined features of the disease suggest that restoring torsinA function could be an excellent candidate for therapeutic intervention.

Here, the authors used C. elegans in a screen to identify FDA-approved drugs that enhance torsinA activity. Using engineered nematode lines expressing human torsinA variants, they identified chemical enhancers of torsinA, including the common antibiotic ampicillin. In fibroblast cells isolated directly from DYT1 patients, normal levels of torsinA function were restored by treatment with ampicillin. Finally, ampicillin treatment reversed a behavioral movement deficit within a well-characterized mouse model of Dyt1 dystonia. This supports the development of ampicillin as a lead theraputic to benefit patients with torsinA defects, such as those with EOTD.

This work highlights the powerful utility of combining model systems to accelerate the translational path for human movement disorders, and reveals the potential for an unexploited new target for drug development. The capacity for ampicillin to activate torsinA function in a variety of bioassays, which include multiple cell types from several species, suggests a conserved molecular mechanism that may be reversed to restore neuronal function. Notably, the torsinA protein is highly expressed in human dopamine-producing neurons, where it is believed to serve a normally protective role. Therefore, the identification of small molecule enhancers of torsinA activity may be beneficial to many patients, in addition to those with dystonia, such as those with Parkinson’s disease.

The identification of small molecule modifiers of torsinA function should enable the development of new drug therapy for neurological disease, such as dystonia. The long-term use of antibiotics is not desirable owing to its potential for creating antibiotic-resistant microorganisms and the eliminatination of necessary probiotics. Therefore, continued investigation should build from these findings to create a more suitable therapy than ampicillin that is a functionally related modifier of torsinA.

2010