Lentiviral Overexpression of GRK6 Alleviates
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            -Dopa–Induced Dyskinesia in Experimental Parkinson’s Disease

Ahmed, M. Rafiuddin; Berthet, Amandine; Bychkov, Eugenii R.; Porras, Grégory; Li, Qin; Bioulac, Bernard; Carl, Yonatan T.; Bloch, Bertrand; Kook, Seunghyi; Aubert, Incarnation; Doveró, Sandra; Doudnikoff, Évelyne; Gurevich, Vsevolod V.; Gurevich, Eugenia V.; Bézard, Erwan

doi:10.1126/scitranslmed.3000664

Cited by 127 publications

(225 citation statements)

References 39 publications

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“…However, simultaneous action of D1 and D2 receptors are required for the therapeutic effect of L-DOPA, as both indirect and direct pathway are required for a proper goaldirected locomotion (62)(63)(64). Consistent with this notion, studies with GRK6 overexpression on L-DOPA behaviors also suggest that a balance between D1Rs and D2Rs is important for antiparkinsonian effects (30). Therefore, we propose that in addition to focusing on particular receptor subtypes, we should also focus on selective activated signaling cascades beyond their stimulation.…”

Section: Discussionsupporting

confidence: 61%

“…Other studies have shown that β-arrestins and GRK6 are overexpressed in mouse and monkey models of PD (43,44), and that lentiviral-mediated overexpression of GRK6 in rodent and monkey models of PD reduces LIDs (30). GRK6, which lies upstream of β-arrestins in the GPCR signaling cascade, presumably promotes β-arrestin-dependent signaling (45)(46)(47).…”

Section: Resultsmentioning

confidence: 99%

“…Animal care was supervised daily by veterinarians skilled in the healthcare and maintenance of nonhuman primates. The MPTP intoxication protocol, the chronic L-DOPA treatment, the clinical assessments, the terminal procedure, and the characterization of the extent of nigrostriatal denervation were conducted as previously published (29)(30)(31)(72)(73)(74). Animals were first rendered parkinsonian with MPTP-hydrochloride (0.2 mg/kg, i.v.…”

Section: Animalsmentioning

confidence: 99%

“…This protocol allowed us to study the impact of βarr2 overexpression upon already established dyskinesia. The four AIM categories [limb, axial, orolingual (ALO) and locomotive] were scored using a validated rating scale (56, 67) for 1 min every 20 min for 3 h by a trained investigator as previously described (29,30). Monkey experimental schedule.…”

Section: Animalsmentioning

confidence: 99%

“…Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias. To moderate this uncontrolled signaling or neuronal excitability, several approaches have been explored such as reducing D1R surface expression (29,30), dampening overactive intracellular signaling (20,23,31,32), and inhibiting A2A (33,34), mGluR5 (35)(36)(37) or NMDA receptors (24,25,(38)(39)(40). Although these targets have clinical potential, several drugs to these targets have either failed clinical trials or have the potential to affect other key CNS physiological processes.…”

mentioning

confidence: 99%

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Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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105

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

105

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Hypermethylation of the G protein‐coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBPα, and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells

Yao

Chen

et al. 2019

FEBS Open Bio

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We previously reported that the expression of G protein‐coupled receptor kinase 6 (GRK6) is significantly downregulated in lung adenocarcinoma (LADC) tissues, and low expression levels of GRK6 are correlated with poor survival prognosis. However, the specific regulatory mechanisms and functions of GRK6 in LADC remain unknown. Here, we report that GRK6 mRNA expression levels are downregulated in LADC tissues compared to those in matched adjacent non‐tumor tissues (P < 0.001). The promoter of the GRK6 gene was found to be hypermethylated in LADC tissues, and its methylation was correlated with both GRK6 expression and pathology grade. GRK6 promoter hypermethylation may predict shorter overall survival. Treatment with 5‐aza‐2′‐deoxycytidine significantly enhanced GRK6 gene expression. Four binding sites of CCAAT/enhancer‐binding protein‐α (C/EBPα) in the CpG island of the GRK6 gene promoter were predicted in silico, of which three sites were further confirmed by ChIP. Decreased binding of C/EBPα to binding sites 1, 3 and 4 of the GRK6 gene promoter was observed in LADC tissues. Inhibition of C/EBPα significantly inhibited GRK6 expression, while overexpression of C/EBPα significantly promoted GRK6 expression. In addition, overexpression of GRK6 significantly suppressed, while GRK6 knockdown promoted cell migration and invasion. Overexpression of GRK6 enhanced E‐cadherin expression and suppressed vimentin expression, and silencing of GRK6 had the opposite effects. Furthermore, ectopic expression of GRK6 significantly decreased matrix metalloproteinase (MMP) 2 and MMP7 protein expression levels. Our findings suggest that hypermethylation of the GRK6 gene promoter suppressed binding of C/EBPα, thereby contributing to the promotion of cell migration and invasion. The methylation status of the GRK6 promoter might be suitable for use as an epigenetic biomarker, and the C/EBPα–GRK6 signaling pathway may be a potential target for LADC.

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Therapeutic Strategies to Combat the Onset and Progression of Neurological Diseases

2013

Metal‐based Neurodegeneration

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Lentiviral Overexpression of GRK6 Alleviates l -Dopa–Induced Dyskinesia in Experimental Parkinson’s Disease

Cited by 127 publications

References 39 publications

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Hypermethylation of the G protein‐coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBPα, and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells

Therapeutic Strategies to Combat the Onset and Progression of Neurological Diseases

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