Objective: The aim of the study was to examine the association between polymorphic variants of GRM3 and GRM5 and Parkinson’s disease (PD) and motor and non-motor symptoms.

Background: Type-3 metabotropic glutamate (mGlu3) receptors exert pleiotropic functions in the CNS depending on their anatomical localization [1]. Presynaptic mGlu3 receptors inhibit glutamate release, whereas postsynaptic mGlu3 receptors boost mGlu5 receptors signaling [1,2]. In addition, activation of mGlu3 receptors in astrocytes stimulates the production of GDNF and TGF-β and drives microglia towards an anti-inflammatory phenotype [3,4].

Method: The study sample included 723 PD patients and 828 age/gender-matched healthy controls. The DNA was extracted from the blood samples and the WES analysis allowed a massive and simultaneous genotyping of all the samples under examination.

Results: The GRM3 gene haplotype was significantly associated with PD [OR 95% CI 3.34 (1.57-7.10); p-value 0.0018]. The mutated variants are rs1527768 (G,A), rs187993 (G,T), rs274622 (T,C), rs724226 (G,A), while rs13242038, rs1468412, rs2228595, rs2237562 and rs906415 are wild-type. The rs60954128 polymorphism of the GRM5 gene is associated with the PD development [OR 95% CI 1.95 (1.16-3.29); p-value 0.0084]. GRM3 and GRM5 genes variants are associated also with PD phenotype, in particular with cardiovascular dysautonomia, cognitive impairment and fatigue.

Conclusion: These findings suggest that mGlu3 and mGlu5 receptors might shape the balance between neurodegeneration and neuroprotection in PD and might be targeted by therapeutic intervention.

References: 1. Bruno V, Caraci F, Copani A, Matrisciano F, Nicoletti F, Battaglia G. The impact of metabotropic glutamate receptors into active neurodegenerative processes: A “dark side” in the development of new symptomatic treatments for neurologic and psychiatric disorders. Neuropharmacology. 2017 Mar 15;115:180-192.
2. Di Menna L, Joffe ME, Iacovelli L, Orlando R, Lindsley CW, Mairesse J, Gressèns P, Cannella M, Caraci F, Copani A, Bruno V, Battaglia G, Conn PJ, Nicoletti F. Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system. Neuropharmacology. 2018 Jan;128:301-313.
3. Battaglia G, Riozzi B, Bucci D, Di Menna L, Molinaro G, Pallottino S, Nicoletti F, Bruno V. Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2015 Feb;74:126-36.
4. Zinni M, Mairesse J, Pansiot J, Fazio F, Iacovelli L, Antenucci N, Orlando R, Nicoletti F, Vaiman D, Baud O. mGlu3 receptor regulates microglial cell reactivity in neonatal rats. J Neuroinflammation. 2021 Jan 6;18(1):13.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-metabotropic-glutamate-receptors-type-3-and-5-in-parkinsons-disease-analysis-of-grm3-and-grm5-genbe-variants/