Treating worms with ampicillin helps restore normal movement
Discovery of an antibiotic's capacity to improve cell function in laboratory tests is providing movement disorder researchers with leads to more desirable molecules with potentially similar traits, according to University of Alabama scientists co-authoring a paper publishing March 10 in the journal Disease Models & Mechanisms.
"It's our hope that this discovery serves as the impetus for a proper clinical trial to evaluate the potential of drugs like ampicillin for early-onset torsion dystonia," said Dr. Guy Caldwell, associate professor of biological sciences at The University of Alabama. Dystonia is, like Parkinson's disease, a movement disorder. Combined, this class of diseases affects millions worldwide. People with early-onset dystonia have one good copy of the gene DYT1, and one problematic copy, in their DNA. These genes contain the information to make a protein called torsinA.
"When proteins go bad, they often cause disease, but they always have a normal function in our cells," Guy Caldwell said. "We looked to find molecules - not necessarily that reversed the mutated form of the protein - but instead enhanced the normal activity of the protein, thereby overcoming the deficiency caused by the mutant."
The UA researchers discovered that ampicillin, a common antibiotic of the penicillin group, serves to activate torsinA, which, in its normal form, appears to protect cells from stresses, such as protein misfolding - a problem known to impact various movement disorders.
Using a nematode animal model designed to evaluate torsinA activity, the UA lab rapidly screened through hundreds of compounds to identify those that were most effective at enhancing torsinA's normally protective function.
"From there, we collaborated with researchers at Harvard and UAB to validate our findings in human patient cells and mice," said Dr. Kim Caldwell, associate professor of biological sciences at UA.
"In human dystonia patient cells, ampicillin was efficacious and restored the patient cells back to the normal function," Kim Caldwell said. "And, the drug restored normal movement to mice that were genetic mimics of dystonia."
Collaborators in the UA-led study were Drs. Xandra O. Breakefield and her colleagues at Harvard and Yuqing Li and his colleagues at The University of Alabama at Birmingham, known as UAB. Dr. Songsong Cao, a former doctoral student in the Caldwell Lab, is the study's lead author; two UA doctoral students, Alexander J. Burdette and Pan Chen; and one former UA student, Amber Clark Buckley, are among the co-authors.
Furthermore, the research shows ampicillin enhances the capacity of torsinA to protect, within animal models, the neurons which produce dopamine from dying. The death of these neurons in human brains leads to the hallmark symptoms of Parkinson's disease.
In a statement accompanying the paper, the researchers caution against the long-term use of an antibiotic in disease treatment.