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
UR - http://www.scopus.com/inward/record.url?scp=85065917222&partnerID=8YFLogxK
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 -