Promising Outcomes of Original Grant:
Our original target validation grant was aimed at deciphering the role of the protein beta-arrestin2 in the manifestation of beneficial versus dyskinetic side-effects of levodopa. We hypothesized that altering beta-arrestin2 expression would alter both levodopa-induced dyskinesia and locomotion. Our hypotheses were proven correct, and we showed that over-expression of beta-arrestin2 reduced the occurrence of dyskinesias but at the same time enhanced locomotion. These results provide us a validated rationale to screen for beta-arrestin2-biased drugs that improve PD symptoms without causing dyskinesias.
Objectives for Supplemental Investigation:
Our compelling results from the target validation grant showed that we could behaviorally differentiate between the beneficial versus the unwanted side-effects of levodopa. We now seek to validate our bilateral model for locomotion and dyskinesias so that we can use our model as a simple and robust screening tool for drugs that inhibit dyskinesias and/or elicit only forward locomotion. In our original target validation grant we used global beta-arrestin2 knockout models and whole striatal over-expression of beta-arrestin2. This approach does not shed light on the specific dopamine receptor subtypes involved in mediating the effects of levodopa. Therefore we propose to use cell-specific approaches to delete or over-express beta-arrestin2 in dopamine receptor neurons. This approach will help us identify the neuronal pathways and the dopamine receptor subtypes that regulate the behavioral outcomes of levodopa administration.
Importance of This Research for the Development of a New PD Therapy:
Our proposed experiments will identify the dopamine receptors involved in the beta-arrestin2-dependent behaviors upon levodopa administration. This will allow us to specifically generate biased beta-arrestin compounds at these receptors that have the potential to elicit locomotion without causing dyskinesias. The simple and robust behavioral screening tool we have generated using our novel model of dyskinesias has the potential to help the PD scientific community to screen for novel PD therapies.
Our goal was to develop pre-clinical models as a facile screening tool for anti-parkinsonian and anti-dyskinetic agents. As proof-of-concept we screened previously characterized anti-dyskinetic agents that have been used in the clinic and found that these agents show similar anti-dyskinetic properties in these models. These data thus provide compelling evidence that the models can be used as a versatile screening tool for drugs/agents that can reduce levodopa-induced dyskinesias or increase locomotion or ideally do both. We are in the process of assessing cell-specific genetic manipulation of beta-arrestin2 in the models and its anti-parkinsonian and anti-dyskinetic effects.