Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Marco Milanese, Francesco Giribaldi, Marcello Melone, Tiziana Bonifacino, Ilaria Musante, Enrico Carminati, Pia I A Rossi, Laura Vergani, Adriana Voci, Fiorenzo Conti, Aldamaria Puliti, Giambattista Bonanno

Research output: Research - peer-reviewArticle

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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 (SOD1G93A), 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 SOD1G93A background (SOD1G93AGrm1crv4/+), by crossing the SOD1G93A mutant mouse with the Grm1crv4/+ mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1G93AGrm1crv4/+ mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1G93A 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 SOD1G93AGrm1crv4/+compared to SOD1G93A 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.

LanguageEnglish
Pages48-59
Number of pages12
JournalNeurobiology of Disease
Volume64
DOIs
StatePublished - Apr 2014

Fingerprint

Amyotrophic Lateral Sclerosis
Disease Progression
Survival
metabotropic glutamate receptor type 1
Glutamic Acid
Motor Neurons
Spinal Cord
Autoreceptors
Spinal Nerves
Metabotropic Glutamate Receptors
Metallothionein
Microglia
Point Mutation
Astrocytes
Neurodegenerative Diseases
Catalase
Superoxide Dismutase
Animal Models
Pharmacology
Pathology

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 mouse

ASJC Scopus subject areas

  • Neurology

Cite this

Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. / Milanese, Marco; Giribaldi, Francesco; Melone, Marcello; Bonifacino, Tiziana; Musante, Ilaria; Carminati, Enrico; Rossi, Pia I A; Vergani, Laura; Voci, Adriana; Conti, Fiorenzo; Puliti, Aldamaria; Bonanno, Giambattista.

In: Neurobiology of Disease, Vol. 64, 04.2014, p. 48-59.

Research output: Research - peer-reviewArticle

Milanese, Marco ; Giribaldi, Francesco ; Melone, Marcello ; Bonifacino, Tiziana ; Musante, Ilaria ; Carminati, Enrico ; Rossi, Pia I A ; Vergani, Laura ; Voci, Adriana ; Conti, Fiorenzo ; Puliti, Aldamaria ; Bonanno, Giambattista. / Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. In: Neurobiology of Disease. 2014 ; Vol. 64. pp. 48-59
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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 (SOD1G93A), 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 SOD1G93A background (SOD1G93AGrm1crv4/+), by crossing the SOD1G93A mutant mouse with the Grm1crv4/+ mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1G93AGrm1crv4/+ mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1G93A 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 SOD1G93AGrm1crv4/+compared to SOD1G93A 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.",
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AU - Bonifacino,Tiziana

AU - Musante,Ilaria

AU - Carminati,Enrico

AU - Rossi,Pia I A

AU - Vergani,Laura

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