Decreased Rhes mRNA levels in the brain of patients with Parkinson's disease and MPTP-treated macaques.

Francesco Napolitano,Erwan Bezard,Micaela Morelli,Sara Migliarini,Daniela Punzo,Emily Booth Warren,Francesco Errico,Qin Li,Massimo Pasqualetti,Alessandro Usiello,Angelo Luigi Vescovi,Marie-Laure Thiolat,Paolo Calabresi,Christine Konradi,Joohyung Lee

doi:10.1371/journal.pone.0181677

Abstract

In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson’s disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.

Highlights

Rhes (RASD2) is a gene encoding for a GTP-binding protein highly enriched in the corpus striatum [1,2,3], and developmentally regulated by thyroid hormones [4, 5]
Rhes binds to and activates mTORC1 signalling in the striatum, which is known to influence the expression of L-DOPA-induced dyskinesia (LID) in rodent Parkinson’s disease (PD) models [17, 18]
To further dissect whether Rhes gene expression might be influenced by the dopamine denervation in an experimental non-human primate model of PD, we evaluated striatal levels of Rhes mRNA in Macaca Mulatta, treated with MPTP

Summary

Introduction

Rhes (RASD2) is a gene encoding for a GTP-binding protein highly enriched in the corpus striatum [1,2,3], and developmentally regulated by thyroid hormones [4, 5]. Rhes binds to and activates mTORC1 signalling in the striatum, which is known to influence the expression of L-DOPA-induced dyskinesia (LID) in rodent PD models [17, 18]. Though a putative link between Rhes and neurodegenerative disorders has been established, this G-protein, by regulating AKT and cAMP/PKA signalling, might play a role in biochemical pathways in the brain of BD and SCZ patients [28,29,30]. In order to investigate the possible alteration of Rhes mRNA expression in neurodegenerative and psychiatric disorders, we evaluated whether its transcript levels might be affected by the diagnosis of PD, SCZ and BD. To further dissect whether Rhes gene expression might be influenced by the dopamine denervation in an experimental non-human primate model of PD, we evaluated striatal levels of Rhes mRNA in Macaca Mulatta, treated with MPTP

Methods

Results

Conclusion