RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models.

Paola Bonsi,Rose E Goodchild,Antonio Pisani,Marcello D'Amelio,Massimo Pasqualetti,Venetia Zachariou,Annalisa Tassone,Maria Meringolo,Nicola B Mercuri,Giulia Ponterio,Erwan Bezard,Evelyne Doudnikoff,Sara Migliarini,Valentina Vanni,Benjamin Dehay,Giuseppina Martella,Giuseppe Sciamanna

doi:10.15252/emmm.201809283

Abstract

Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β‐arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9‐2 and spinophilin. Further, we show that genetic depletion of RGS9‐2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9‐2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease‐modifying therapeutics to this incurable neurological disorder.

Highlights

Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia
In order to analyze the molecular mechanisms of DRD2 dysfunction, we utilized the Tor1a+/À mouse model that mimics the loss of function effect of the DYT1 dystonia TOR1A mutation
Based on the well-characterized reciprocal regulatory relationship between GPCRs and regulator of G protein signaling (RGS) proteins, we examined whether RGS protein levels were affected and might give further insight on the nature of the impairment of D2R-mediated transmission in DYT1 mutant mice

Summary

Introduction

Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. The mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. We identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt mice. This occurs through increased lysosomal degradation, controlled by competition between b-arrestin 2 and D2 receptor binding proteins. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data open up novel avenues for disease-modifying therapeutics to this incurable neurological disorder

Methods

Results

Discussion

Conclusion