title: RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease.
abstract: Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated l-DOPA/benserazide treatment caused an elevation of RGS4 mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4 mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4 mRNA in the striatum by continuous infusion of RGS4 antisense oligonucleotides, via implanted osmotic mini-pumps, during l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated l-DOPA-induced elevations of PPE-B mRNA and dopamine-stimulated [(35)S]GTPγS binding, a marker used for measuring dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4 proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4 mRNA levels in l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4 proteins could prove beneficial in the treatment of dyskinesia in PD.
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: daniel.ko@u-bordeaux.fr.
authors: Wai Kin D
authors: WK
authors: Ko
authors: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors: Marie-Laure
authors: ML
authors: Martin-Negrier
authors: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors: Erwan
authors: E
authors: Bezard
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Alan R
authors: AR
authors: Crossman
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: Paula
authors: P
authors: Ravenscroft
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology* / Q000628:therapy; D004745:Enkephalins / Q000378:metabolism; D007839:Functional Laterality; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D011498:Protein Precursors / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000978:Antiparkinson Agents; D004745:Enkephalins; D016376:Oligonucleotides, Antisense; D011498:Protein Precursors; D020710:RGS Proteins; D012333:RNA, Messenger; C098799:RGS4 protein; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin
keywords: Abnormal involuntary movements; Antisense oligonucleotides; Parkinson's disease; RGS4; l-DOPA-induced dyskinesia