Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease due to motor neuron (MN) loss. The mechanisms causing selective MN death are largely unknown, thus prejudicing successful pharmacological treatments. Major causes of MN damage are effects downstream of the abnormal glutamate (Glu) neurotransmission. Group I metabotropic Glu receptors (mGluR1, mGluR5) actively contribute to the excitotoxicity in ALS and represent druggable molecular targets. We previously demonstrated that halving mGluR1 or mGluR5 expression in the widely studied SOD1 G93A mouse model of ALS had a positive impact on disease onset, clinical progression and survival, as well as on cellular and biochemical parameters altered in ALS. Whereas these effects were similar in female and male mGluR1 heterozygous SOD1 G93A mice, only male mGluR5 heterozygous SOD1 G93A mice showed improved motor skills during disease progression. To further validate the role of Group I mGluRs in ALS, we generated in this study mGluR1 or mGluR5 null mice expressing the SOD1 G93A mutation (SOD1 G93A Grm1 crv4/crv4 or SOD1 G93A Grm5 −/− , respectively). SOD1 G93A Grm1 crv4/crv4 mice showed early and progressive motor impairments and died even before SOD1 G93A mice, while SOD1 G93A Grm5 −/− mice exhibited delayed disease onset, longer survival, and ameliorated motor skills than SOD1 G93A mice. No difference between female and male SOD1 G93A Grm5 −/− mice were observed. These effects were associated with enhanced MN preservation and decreased astrocytic and microglial activation. Our results strongly support the assumption that constitutively lowering of mGluR5 expression has a positive impact in mice with ALS by counteracting the abnormal Glu transmission and this could be a potentially effective pharmacological target in ALS.
| Original language | English |
|---|---|
| Pages (from-to) | 79-92 |
| Number of pages | 14 |
| Journal | Neurobiology of Disease |
| Volume | 129 |
| DOIs | |
| Publication status | Published - Sep 1 2019 |
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Keywords
- Amyotrophic lateral sclerosis
- Behaviour
- Genetic ablation
- Histology, disease progression
- In-vivo
- Metabotropic glutamate type 5 receptor
- SOD1 mouse
ASJC Scopus subject areas
- Neurology
Cite this
In-vivo genetic ablation of metabotropic glutamate receptor type 5 slows down disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. / Bonifacino, Tiziana; Provenzano, Francesca; Gallia, Elena; Ravera, Silvia; Torazza, Carola; Bossi, Simone; Ferrando, Sara; Puliti, Aldamaria; Van Den Bosch, Ludo; Bonanno, Giambattista; Milanese, Marco.
In: Neurobiology of Disease, Vol. 129, 01.09.2019, p. 79-92.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In-vivo genetic ablation of metabotropic glutamate receptor type 5 slows down disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis
AU - Bonifacino, Tiziana
AU - Provenzano, Francesca
AU - Gallia, Elena
AU - Ravera, Silvia
AU - Torazza, Carola
AU - Bossi, Simone
AU - Ferrando, Sara
AU - Puliti, Aldamaria
AU - Van Den Bosch, Ludo
AU - Bonanno, Giambattista
AU - Milanese, Marco
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease due to motor neuron (MN) loss. The mechanisms causing selective MN death are largely unknown, thus prejudicing successful pharmacological treatments. Major causes of MN damage are effects downstream of the abnormal glutamate (Glu) neurotransmission. Group I metabotropic Glu receptors (mGluR1, mGluR5) actively contribute to the excitotoxicity in ALS and represent druggable molecular targets. We previously demonstrated that halving mGluR1 or mGluR5 expression in the widely studied SOD1 G93A mouse model of ALS had a positive impact on disease onset, clinical progression and survival, as well as on cellular and biochemical parameters altered in ALS. Whereas these effects were similar in female and male mGluR1 heterozygous SOD1 G93A mice, only male mGluR5 heterozygous SOD1 G93A mice showed improved motor skills during disease progression. To further validate the role of Group I mGluRs in ALS, we generated in this study mGluR1 or mGluR5 null mice expressing the SOD1 G93A mutation (SOD1 G93A Grm1 crv4/crv4 or SOD1 G93A Grm5 −/− , respectively). SOD1 G93A Grm1 crv4/crv4 mice showed early and progressive motor impairments and died even before SOD1 G93A mice, while SOD1 G93A Grm5 −/− mice exhibited delayed disease onset, longer survival, and ameliorated motor skills than SOD1 G93A mice. No difference between female and male SOD1 G93A Grm5 −/− mice were observed. These effects were associated with enhanced MN preservation and decreased astrocytic and microglial activation. Our results strongly support the assumption that constitutively lowering of mGluR5 expression has a positive impact in mice with ALS by counteracting the abnormal Glu transmission and this could be a potentially effective pharmacological target in ALS.
AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease due to motor neuron (MN) loss. The mechanisms causing selective MN death are largely unknown, thus prejudicing successful pharmacological treatments. Major causes of MN damage are effects downstream of the abnormal glutamate (Glu) neurotransmission. Group I metabotropic Glu receptors (mGluR1, mGluR5) actively contribute to the excitotoxicity in ALS and represent druggable molecular targets. We previously demonstrated that halving mGluR1 or mGluR5 expression in the widely studied SOD1 G93A mouse model of ALS had a positive impact on disease onset, clinical progression and survival, as well as on cellular and biochemical parameters altered in ALS. Whereas these effects were similar in female and male mGluR1 heterozygous SOD1 G93A mice, only male mGluR5 heterozygous SOD1 G93A mice showed improved motor skills during disease progression. To further validate the role of Group I mGluRs in ALS, we generated in this study mGluR1 or mGluR5 null mice expressing the SOD1 G93A mutation (SOD1 G93A Grm1 crv4/crv4 or SOD1 G93A Grm5 −/− , respectively). SOD1 G93A Grm1 crv4/crv4 mice showed early and progressive motor impairments and died even before SOD1 G93A mice, while SOD1 G93A Grm5 −/− mice exhibited delayed disease onset, longer survival, and ameliorated motor skills than SOD1 G93A mice. No difference between female and male SOD1 G93A Grm5 −/− mice were observed. These effects were associated with enhanced MN preservation and decreased astrocytic and microglial activation. Our results strongly support the assumption that constitutively lowering of mGluR5 expression has a positive impact in mice with ALS by counteracting the abnormal Glu transmission and this could be a potentially effective pharmacological target in ALS.
KW - Amyotrophic lateral sclerosis
KW - Behaviour
KW - Genetic ablation
KW - Histology, disease progression
KW - In-vivo
KW - Metabotropic glutamate type 5 receptor
KW - SOD1 mouse
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UR - http://www.scopus.com/inward/citedby.url?scp=85065917222&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2019.05.007
DO - 10.1016/j.nbd.2019.05.007
M3 - Article
AN - SCOPUS:85065917222
VL - 129
SP - 79
EP - 92
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -