Dyskinesia (abnormal involuntary movements) represents one of the major obstacles in the current drug therapy for Parkinson’s disease. A complication of prolonged administration of levodopa (L-dopa), dyskinesia is thought to derive from changes in the molecular machinery of neurons in the striatum that receive dopamine inputs.Genetically modified mice – an essential tool of clinical research – may offer an opportunity to identify the primary determinants of cellular changes underlying dyskinesia. However, a valid model of levodopa-induced dyskinesia in the mouse has thus far not been available. For this reason, Parkinson’s researchers led by Gilberto Fisone, Ph.D., of the Karolinska Institute in Sweden, are developing and validating a mouse model of dyskinesia.
Fisone and his colleagues have previously found that, in the rat, dyskinesia is accompanied by abnormally high levels of phosphorylated DARPP-32, the “master molecule” through which dopamine signals. The researchers will use the newly developed mouse model of dyskinesia to examine how abnormal DARPP-32 phosphorylation is involved. They will also identify any changes at the level of specific signaling pathways and/or neurotransmitter systems that might be responsible for the aberrant phosphorylation of DARPP-32 associated with dyskinesia. This information will be used to select a number of candidate drugs that will be screened for efficacy in laboratory tests, thereby providing a basis for the design of novel pharmacological treatments for Parkinson’s disease. The battery of tests the researchers have designed will serve as a paradigm for future studies aimed at screening novel Parkinson’s treatments in mice.
Similarly, acetylcholine has been shown to modulate dopamine signaling, and drugs that increase acetylcholine levels (cholinergic agents, such as those currently used to treat Alzheimer’s disease) have shown some benefit in lessening Parkinson’s-like involuntary movements. Elucidating the molecular mechanisms through which acetylcholine acts will reveal new targets for developing drugs that regulate these processes.To take this vast reservoir of knowledge to the next step in the process of developing new therapies, our laboratories are producing genetically altered mice -i.e., mice that either express or fail to express genes that encode proteins of interest. A mouse that has been genetically altered to carry a new gene is said to be “transgenic.” A mouse that has been genetically altered so that one of its own genes has been deleted (and can no longer be expressed) is called a “knockout.” By then analyzing the biochemistry and behavior of these transgenic and knock-out mice Stern Center researchers are better able to understand how specific proteins interact with the dopamine system, and what role each plays in the development of Parkinsonian symptoms.
Solutions Within Reach
These are just a few of the many lines of research our Center is pursuing in its quest to identify novel proteins and substances that can be used to develop drug therapies in the battle against Parkinson’s disease. These investigations capitalize on the team’s vast knowledge of dopamine signaling systems in the brain, and employ a multidisciplinary approach that advances the research in the most efficient ways possible. New drug targets are months, not years, away.
Clearly, this outstanding team of scientists has the right stuff to make the dream of effective new Parkinson’s treatments a reality. With the right resources supporting them, the dream will become a reality sooner rather than later.