Objective/Rationale:
Beta-arrestins were originally identified as proteins that attenuate the signaling function of the large class of receptors to which dopamine receptors belong. However, recently, beta-arrestins have been shown to promote distinct receptor signaling through their ability to organize novel intracellular complexes to mediate distinct cellular and physiological processes including dopamine dependent locomotion. This study plans to validate the role of beta-arrestins in levodopa induced locomotion in pre-clinical models of PD and determine their possible role in the manifestation of dyskinesia.
Project Description:
To test our hypotheses, we will use the Dopamine-Deficient DAT-KO (DDD) pre-clinical model of acute PD symptoms to delete or overexpress beta-arrestin2 (Barr2) by genetic (Cre/LoxP) and viral approaches respectively. These manipulations will be designed to delete or over-express Barr2 in striatonigral (D1) or striatopallidal (D2) medium spiny neurons (MSNs) of the striatum, the two major cell populations responsible for the actions of levodopa. Lastly, based on our preliminary results we will further validate that chronic L-DOPA treatment exacerbates the “paw dyskinesia/vertical activity” phenotype in the DDD pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our central hypothesis is that the beneficial effects of levodopa treatment are mediated by beta-arrestin2 signaling, whereas dyskinesias result from the classical G protein-dependent signaling of dopamine receptors; consequently much better therapies will result by biasing dopamine receptor signaling towards the beta-arrestin pathway. These studies will provide a validated rationale for the eventual development of novel beta-arrestin biased DA receptor agonists that selectively activate the beta-arrestin versus the G protein pathway, which would dramatically improve the quality of life for Parkinsonian patients without causing dyskinesias.
Final Outcome
We hypothesized that beta-arrestin2 (BARR2) mediates the beneficial locomotor effects of L-DOPA and at the same time inhibits dyskinesias. We used a Dopamine-Deficient DAT-KO (DDD) model of PD to test our hypothesis. We either deleted or over-expressed BARR2 in the DDD pre-clinical model and tested its effect on L-DOPA induced locomotion and dyskinesias. We observed that deletion of BARR2 increased dyskinesias and reduced the locomotor response induced by L-DOPA. However, over-expressing Barr2 enhanced forward locomotion but inhibited dyskinesias induced by L-DOPA. These results confirm our hypothesis and validate a crucial role for BARR2 in L-DOPA induced locomotion and dyskinesias.