Alterations in mGluR5 Expression and Signaling in Lewy Body Disease and in Transgenic Models of Alpha-Synucleinopathy – Implications for Excitotoxicity

Price, D. L.; Rockenstein, Edward; Ubhi, Kiran; Phung, Van; MacLean-Lewis, Natalie; Askay, David A.; Cartier, Anna; Spencer, Brian; Patrick, Christina; Desplats, Paula; Ellisman, Mark H.; Masliah, Eliezer

doi:10.1371/journal.pone.0014020

Cited by 72 publications

(65 citation statements)

References 88 publications

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“…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%

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.

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: Resultsmentioning

confidence: 99%

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.

105

View full text Add to dashboard Cite

show abstract

“…While in the previous study we analyzed PDGF-α-syn (line D) mice [19], for this new study we investigated the mThy1-α-syn (line 61), as well as crosses with the mThy1-APP mutant tg mouse model of DLB. This bigenic mThy1-α-syn/APP mutant tg line is new and has not been reported before.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5 – implications for dementia with Lewy bodies

Overk

Cartier

Shaked

et al. 2014

Mol Neurodegeneration

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BackgroundIn dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.ResultsWe generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.ConclusionsTogether, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB.

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“…Previous research using [ 35 S]GTPcS (guanosine 5 0 -O-[c-thio]triphosphate) functional binding autoradiography has demonstrated a similar process in PD, whereby compensatory mechanisms maintain dopaminergic neurotransmission, despite a reduction in D2 receptor density, via increases in D2 receptor-G protein signal transduction in the caudate (Farkas et al 2012). Moreover, previous postmortem brain research has shown an increase in mGluR5 immunoreactivity in the putamen in patients with PD, implying that upregulation of these receptors also occurs in PD (Price et al 2010). Despite the clear loss of neurons within the putamen and caudate in our study, the total cell count was essentially unchanged in HD samples compared with control samples, suggesting reactive gliosis.…”

Section: Discussionmentioning

confidence: 94%

“…Data from murine models of HD found no change in the density of this receptor in the brains of symptomatic animals (Cha et al 1998), whereas brains of patients with PD show increased mGluR5 levels (Price et al 2010). Given the similarity in the clinical features of HD and PD with levodopa-induced dyskinesia (PD-LID), we hypothesized that the pattern of mGluR5 density, as well as Enk-and SP-containing neurons, would be similar in the basal ganglia of patients with these two conditions.…”

Section: Introductionmentioning

confidence: 98%

Decrease of mGluR5 receptor density goes parallel with changes in enkephalin and substance P immunoreactivity in Huntington’s disease: a preliminary investigation in the postmortem human brain

et al. 2014

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Group 1 metabotropic glutamate subtype 5 receptors (mGluR5) contribute to the control of motor behavior by regulating the balance between excitation and inhibition of outputs in the basal ganglia. The density of these receptors is increased in patients with Parkinson's disease and motor complications. We hypothesized that similar changes may occur in Huntington's disease (HD) and aimed at testing this hypothesis in a preliminary experimental series in postmortem human brain material obtained from HD patients. Using autoradiography, we analyzed mGluR5 density in the putamen, caudate nucleus and cerebellum (control region) in postmortem tissue samples from three patients with HD and three controls with two mGluR5-specific radioligands ([(3)H]ABP688 and [(11)C]ABP688). The density of enkephalin (Enk)- or substance P (SP)-containing neurons was assessed using immunohistochemical and cell-counting methods. [(3)H]ABP688 binding in HD was reduced in the caudate (-70.4 %, P < 0.001), in the putamen (-33.3 %, P = 0.053), and in the cerebellum (-8.79 %, P = 0.930) vs controls. Results with [(11)C]ABP688 were similar; there was good correlation between [(11)C]ABP688 and [(3)H]ABP688 binding ratios. Total cell density was similar in all three brain regions in HD patients and controls. Neuronal density was 69 % lower in the caudate (P = 0.002) and 64 % lower in the putamen (P < 0.001) of HD patients vs controls. Both direct and indirect pathways were affected, with ≥ 90 % decrease in the density of Enk- and SP-containing neurons in the caudate and putamen of HD patients vs controls (P < 0.001). In contrast to earlier observations in PD, in HD, compared to controls, the mGluR5 density was significantly lower in the caudate nucleus. The decrease in neuronal density suggests that neuronal loss was largely responsible for the observed decrease in mGluR5.

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Alterations in mGluR5 Expression and Signaling in Lewy Body Disease and in Transgenic Models of Alpha-Synucleinopathy – Implications for Excitotoxicity

Cited by 72 publications

References 88 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

Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5 – implications for dementia with Lewy bodies

Decrease of mGluR5 receptor density goes parallel with changes in enkephalin and substance P immunoreactivity in Huntington’s disease: a preliminary investigation in the postmortem human brain

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