An m<scp>G</scp>lu4‐<scp>P</scp>ositive <scp>A</scp>llosteric <scp>M</scp>odulator <scp>A</scp>lleviates <scp>P</scp>arkinsonism in <scp>P</scp>rimates

Charvin, Delphine; Paolo, Thérèse Di; Bézard, Erwan; Grégoire, Laurent; Takano, Akihiro; Duvey, Guillaume; Pioli, Elsa Y.; Halldin, Christer; Medori, Rossella; Conquet, François

doi:10.1002/mds.27462

Cited by 50 publications

(34 citation statements)

References 101 publications

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“…Of note, GRM4 agonists not only downregulate IL23, but also increase IL12. Foliglurax (46), a novel positive allosteric activator of GRM4, is currently in phase II trials for Parkinson disease (NCT03162874A). In summary, our findings identify a non-cell-autonomous pathway linking GRM4 to the proinflammatory IL23-IL12 axis, with the potential to be therapeutically targeted in osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

et al. 2019

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The glutamate metabotropic receptor 4 ( GRM4 ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4 − / − genetargeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1 +/ − mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12 . Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23 −/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These fi ndings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinfl ammatory IL23/IL12 axis. SIGNIFICANCE:Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non-cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.Osteosarcoma is an aggressive primary malignant tumor of the bone and a signifi cant cause of cancer-related death in the young. Patients are commonly treated with multimodal approaches, including surgery and adjuvant chemotherapy. Few effective systemic therapies have emerged in the last four decades for relapsed or metastatic osteosarcoma ( 1, 2 ). Osteosarcomas represent a promising indication for strategies that target the immune system ( 2 ); however, a recent clinical trialResearch.on July 16, 2020. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M. Kansara, K. Thomson, P. Pang, D.M. Thomas Study supervision: M. Kansara, D.M. ThomasResearch.on July 16, 2020.

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Section: Discussionmentioning

confidence: 99%

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

et al. 2019

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“…The presence of AS aggregates in LB inclusions of diseased brains suggests dysfunctional proteostasis due to numerous factors including gene mutations, post-translational modifications, external toxins, neuroinflammation, oxidative stress and age-related dysfunction of proteolysis [41]. These aberrant forms of AS, especially the soluble oligomeric forms, were identified as the main culprit of cell death [42].…”

Section: Restoration Of As Proteostasismentioning

confidence: 99%

The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson’s Disease

et al. 2020

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Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson’s disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.

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“…Analysis by a one-tissue compartment model indicated V T ranging from 4.4 mL g −1 in cerebellum to 6.3 mL g −1 in striatum, and 7.7 mL g −1 in thalamus. Brain penetration of the mGluR4 positive allosteric modulator PXT002331 was confirmed in occupancy studies using [ 11 C]PXT012253 ( 93 ) in macaque monkeys [ 218 ]. Recently, the Brownell group developed a [ 18 F]-labelled version, namely N -(4-chloro-3-(([ 18 F]fluoromethyl- d 2 )thio)phenyl)picolinamide for imaging mGluR4 in the brain [ 220 ].…”

Section: Glutamate Receptorsmentioning

confidence: 96%

“…Electron microscopic examination localized the receptor to presynpaptic boutons of type I and type II synapses. Activation of the mGluR4 inhibits the release of GABA and glutamate in parts of the basal ganglia, while tending to decrease excitatory transmission in cerebral cortex, thus drawing attention to it as a possible therapeutic target in Parkinson’s disease (see [ 218 ]).…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

Cited by 50 publications

References 101 publications

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson’s Disease

A Review of Molecular Imaging of Glutamate Receptors

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