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Title: RGS proteins in experimental Parkinsonism and L-DOPA-induced dyskinesia
Author: Ko, Daniel
ISNI:       0000 0004 2724 0194
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder producing a clinical syndrome of bradykinesia, rigidity and resting tremor. These motor symptoms appear due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and loss of dopamine in the striatum, which subsequently leads to an imbalance of the basal ganglia motor circuit. The most effective pharmacological treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the immediate metabolic precursor of dopamine, which effectively restores motor function. L-DOPA is catabolised into dopamine and replaces neurotransmitter loss in PD. However, long-term L-DOPA treatment leads to abnormal involuntary movements (AIMs), such as L-DOPA-induced dyskinesia (LID), which reduces the quality of life in PD patients. Currently, there are no reliable pharmacological treatments for these motor complications. Clinical and preclinical studies have shown that development and expression of LID is linked to unregulated dopamine release and plasticity-induced changes of striatal dopaminergic and non-dopaminergic signalling pathways. The activities of these pathways can be modulated by neurotransmitter receptors of a specific classification, the G-protein-coupled receptor (GPCR) family. In turn, GPCRs are regulated by certain endogenous proteins, the regulators of G-protein signalling (RGS) proteins. Numerous RGS protein subtypes are expressed in the striatum but their roles in PD and LID remain poorly understood. Given the modulatory function of RGS proteins in the striatum, these endogenous factors may have pathophysiological roles in the expression of motor symptoms in PD and LID. The studies presented in this thesis investigated the roles of RGS proteins in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and LID. Rats received unilateral 6-OHDA lesions of the right medial forebrain bundle to induce severe dopamine denervation. L-DOPA/benserazide (6/15 mg/kg) was then administered once daily for at least 21 days to induce stable abnormal involuntary movements (AIMs). In Chapter 2 of this thesis, increased levels of RGS2 and RGS4 mRNA were found in the rostral striatum of the unilateral 6-OHDA-lesioned rat model of LID. Moreover, elevated levels of RGS4 mRNA were specific to sensorimotor regions and positively correlated with AIMs severity. These molecular and behavioural data suggest that RGS4 proteins are involved in the expression of LID. In Chapters 3 and 4, behavioural studies conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that acute inhibition of striatal RGS4 proteins reduced the expression of AIMs and improved overall motor function. Moreover, repeated de novo treatment with RGS4 protein inhibitors, in combination with L-DOPA, attenuated the development of AIMs and reduced the overexpression of preproenkephalin-B, a molecular marker of LID. These behavioural and molecular data suggest that blockade of RGS4 proteins can reduce the induction of LID. In Chapter 5, in vivo microdialysis conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that systemic administration of RGS4 protein inhibitors, in combination with L-DOPA, attenuated unregulated striatal dopamine efflux. These data suggest that RGS4 proteins may regulate specific G-protein coupled receptors, such as 5-HT1A receptors, that modulate striatal dopamine release. In conclusion, the work presented in this thesis shows that RGS4 proteins play a pathophysiological role in the expression and development of LID. These proteins could mediate regulation of key neurotransmitter receptors involved in LID, making them a potential therapeutic target for the development of future treatments.
Supervisor: Crossman, Alan; Ravenscroft, Paula Sponsor: Biotechnology and Biological Sciences Research Council ; Motac neuroscience
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RGS proteins ; Parkinson's disease ; L-DOPA-induced dyskinesia ; RGS4 ; 6-hydroxydopamine