(P109.02) Identification of GPR139 as an attenuator of LID through striatal interneuron transcriptional profiling

Society for Neuroscience Global Connectome, 2021

Dustin R. Zuelke, Katelyn Kennedy, Patrick Barkaus, and Andreas H. Kottmann

Cholinergic interneurons (CINs) of the striatum have been recognized as a key mediator of L-dopa induced dyskinesia. We have previously shown that the Shh pathway attenuates L-Dopa induced dyskinesia (LID) in parkinsonian rodent and macaque models of Parkinson’s disease (PD) in a mechanism that impinges on CIN activity (Malave et al., 2020, BioRX: https://doi.org/10.1101/2020.03.09.983759). The predominant source of Shh for CIN are dopaminergic neurons (DANs) located in the ventral midbrain and are the same population of neurons that degenerate in PD. The downstream transcriptional targets of Shh in CINs are not well defined. We utilized the immunoprecipitation technique, translating ribosome affinity purification (TRAP), to isolate mRNA from CINs for RNAseq in mice with and without Shh from DAN. CIN TRAP extractions were verified by qPCR and had enrichment of the CIN specific transcripts ChAT, GDNF, VAChT, M4, and M2 as well as depletion of the non-CIN transcripts M1 and Parv. The results from the RNAseq analysis identified the orphan G-coupled protein receptor GPR139 as a potential target for further investigation. First, we found that GPR139 is differentially expressed at the protein level in CIN in mice with and without Shh from DAN. GPR139 receptor agonism has been shown to block mu-opioid receptor activation by morphine and fentanyl. Interestingly, mu-opioid receptor antagonism has been shown previously to attenuate LID in animal models of PD. In a proof of principle study, we utilized the aphakia model of PD to ascertain if chronic L-dopa dosing paired with the GPR139 agonist JNJ-63533054 could attenuate the presentation and histological markers of LID. We find in preliminary results that GPR139 agonism reduces the appearance of three-paw dyskinesia in the aphakia model of PD. Histologically, the LID severity marker pERK is reduced with chronic GPR139 agonism in CIN. These results suggest that the transcriptional target of Shh, GPR139 attenuates expression of LID through a CIN resident mechanism. Further studies are needed to clarify the effects of GPR139 on CIN physiology and to determine the mechanism by which GPR139 impinges on LID formation and expression.