title: Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1(G93A)), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1(G93A) background (SOD1(G93A)Grm1(crv4/+)), by crossing the SOD1(G93A) mutant mouse with the Grm1(crv4/+) mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1(G93A)Grm1(crv4/+) mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1(G93A) mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1(G93A)Grm1(crv4/+)compared to SOD1(G93A) mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors.
authors.affiliation: Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.affiliation: Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giribaldi
authors.affiliation: Department of Experimental and Clinical Medicine, Unit of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, Italy; Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Melone
authors.affiliation: Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bonifacino
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Medical Genetics Unit, University of Genoa, Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Musante
authors.affiliation: Department of Earth, Environment and Life Sciences, University of Genoa, Genoa Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Carminati
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Medical Genetics Unit, University of Genoa, Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Pia I A
authors.initials: PI
authors.lastname: Rossi
authors.affiliation: Department of Earth, Environment and Life Sciences, University of Genoa, Genoa Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Vergani
authors.affiliation: Department of Earth, Environment and Life Sciences, University of Genoa, Genoa Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Voci
authors.affiliation: Department of Experimental and Clinical Medicine, Unit of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, Italy; Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy.
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Conti
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Medical Genetics Unit, University of Genoa, Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Aldamaria
authors.initials: A
authors.lastname: Puliti
authors.affiliation: Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy. Electronic address: bonanno@pharmatox.unige.it.
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C578936:Grm5 protein, mouse; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C000606290:SOD1 protein, human; C493396:Slc1a2 protein, mouse; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D008668:Metallothionein; D002374:Catalase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Disease development; Glutamate transmission; Metabotropic glutamate type 1 receptor; Metabotropic glutamate type 1 receptor knocking down; Metabotropic glutamate type 5 receptor; SOD1(G93A) mouse