Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson's disease

Luisa Di Menna; Marika Alborghetti; Maria Ilenia De Bartolo; Marina Borro; Giovanna Gentile; Manuela Zinni; Matteo Bologna; Carolina Cutrona; Giovanna D'Errico; Tiziana Imbriglio; Domenico Bucci; Sara Merlo; Roxana Paula Ginerete; Rosamaria Orlando; Federica Carrillo; Giorgio Fortunato; Milena Cannella; Maria Angela Sortino; Julien Pansiot; Olivier Baud; Ferdinando Nicoletti; Valeria Bruno; Maurizio Simmaco; Francesco Ernesto Pontieri; Edoardo Bianchini; Domiziana Rinaldi; Amalia de Curtis; Giovanni De Gaetano; Licia Iacoviello; Teresa Esposito; Alfredo Berardelli; Giuseppe Battaglia

doi:10.1038/s41531-024-00860-6

Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson's disease

NPJ Parkinsons Dis. 2025 Jan 4;11(1):9. doi: 10.1038/s41531-024-00860-6.

Authors

Luisa Di Menna^#¹, Marika Alborghetti^#^{2

3}, Maria Ilenia De Bartolo^#⁴, Marina Borro³, Giovanna Gentile³, Manuela Zinni⁵, Matteo Bologna^{2

4}, Carolina Cutrona², Giovanna D'Errico¹, Tiziana Imbriglio¹, Domenico Bucci¹, Sara Merlo⁶, Roxana Paula Ginerete¹, Rosamaria Orlando¹, Federica Carrillo⁷, Giorgio Fortunato⁷, Milena Cannella¹, Maria Angela Sortino⁸, Julien Pansiot⁵, Olivier Baud^{5

9

10}, Ferdinando Nicoletti^{1

11}, Valeria Bruno^{1

11}, Maurizio Simmaco³, Francesco Ernesto Pontieri³, Edoardo Bianchini^{3

12}, Domiziana Rinaldi³, Amalia de Curtis¹³, Giovanni De Gaetano¹³, Licia Iacoviello^{13

14}, Teresa Esposito^{1

7}, Alfredo Berardelli^{15

16}, Giuseppe Battaglia^{1

11}

Affiliations

¹ Department of Molecular Pathology, IRCCS Neuromed, Pozzilli, Italy.
² Departments of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
³ Neuroscience, Mental Health, and Sensory Organs Clinical Neurophysiology, Sapienza University of Rome, Rome, Italy.
⁴ Department of Clinical Neurophysiology, IRCCS Neuromed, Pozzilli, Italy.
⁵ Inserm UMR1141 NeuroDiderot, Université Paris Cité, Paris, France.
⁶ Department of Drug and Health Sciences, University of Catania, Catania, Italy.
⁷ Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, National Research Council, Naples, Italy.
⁸ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
⁹ Department of Neonatal Medicine, Cochin-Port Royal Hospital, FHU PREMA, AP-HP Centre, Paris, France.
¹⁰ Université Paris Cite, CRESS, Obstetrical Perinatal and Pediatric Epidemiology Research Team, EPOPE, French Institute for Medical Research and Health INSERM, INRAE, 75014, Paris, France.
¹¹ Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
¹² AGEIS, Université Grenoble Alpes, 38000, Grenoble, France.
¹³ Department of Epidemiology and Prevention, IRCCS Neuromed, 86077, Pozzilli, Italy.
¹⁴ Department of Medicine and Surgery, LUM University, 70010, Casamassima, Bari, Italy.
¹⁵ Departments of Human Neurosciences, Sapienza University of Rome, Rome, Italy. alfredo.berardelli@uniroma1.it.
¹⁶ Department of Clinical Neurophysiology, IRCCS Neuromed, Pozzilli, Italy. alfredo.berardelli@uniroma1.it.

^# Contributed equally.

Abstract

Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson's disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3^-/- mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3^-/- mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.

Abstract

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