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. 2014-10-01; 70: 138-148
DOI: 10.1016/j.nbd.2014.06.013
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1. Neurobiol Dis. 2014 Oct;70:138-48. doi: 10.1016/j.nbd.2014.06.013. Epub 2014 Jun
24.
RGS4 is involved in the generation of abnormal involuntary movements in the
unilateral 6-OHDA-lesioned rat model of Parkinson’s disease.
Ko WK(1), Martin-Negrier ML(2), Bezard E(2), Crossman AR(3), Ravenscroft P(3).
Author information:
(1)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: .
(2)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France.
(3)Faculty of Life Sciences, University of Manchester, Manchester, UK.
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.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2014.06.013
PMID: 24969021 [Indexed for MEDLINE]