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RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease.
Neurobiol Dis. 2014 Oct; 70:138-48.ND

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+Show Affiliations

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.Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.Faculty of Life Sciences, University of Manchester, Manchester, UK.Faculty of Life Sciences, University of Manchester, Manchester, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24969021

Citation

Ko, Wai Kin D., et al. "RGS4 Is Involved in the Generation of Abnormal Involuntary Movements in the Unilateral 6-OHDA-lesioned Rat Model of Parkinson's Disease." Neurobiology of Disease, vol. 70, 2014, pp. 138-48.
Ko WK, Martin-Negrier ML, Bezard E, et al. RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease. Neurobiol Dis. 2014;70:138-48.
Ko, W. K., Martin-Negrier, M. L., Bezard, E., Crossman, A. R., & Ravenscroft, P. (2014). RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease. Neurobiology of Disease, 70, 138-48. https://doi.org/10.1016/j.nbd.2014.06.013
Ko WK, et al. RGS4 Is Involved in the Generation of Abnormal Involuntary Movements in the Unilateral 6-OHDA-lesioned Rat Model of Parkinson's Disease. Neurobiol Dis. 2014;70:138-48. PubMed PMID: 24969021.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease. AU - Ko,Wai Kin D, AU - Martin-Negrier,Marie-Laure, AU - Bezard,Erwan, AU - Crossman,Alan R, AU - Ravenscroft,Paula, Y1 - 2014/06/24/ PY - 2014/05/19/received PY - 2014/06/15/revised PY - 2014/06/17/accepted PY - 2014/6/28/entrez PY - 2014/6/28/pubmed PY - 2015/4/22/medline KW - Abnormal involuntary movements KW - Antisense oligonucleotides KW - Parkinson's disease KW - RGS4 KW - l-DOPA-induced dyskinesia SP - 138 EP - 48 JF - Neurobiology of disease JO - Neurobiol Dis VL - 70 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/24969021/RGS4_is_involved_in_the_generation_of_abnormal_involuntary_movements_in_the_unilateral_6_OHDA_lesioned_rat_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(14)00177-6 DB - PRIME DP - Unbound Medicine ER -