Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons

Jurate Lasiene, Okiru Komine, Noriko Fujimori-Tonou, Berit Powers, Fumito Endo, Seiji Watanabe, Jin Shijie, John Ravits, Philip Horner, Hidemi Misawa, Koji Yamanaka

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Abstract

INTRODUCTION: Increasing evidence implicates the role of the cell types surrounding motor neurons, such as interneurons and glial cells, in non-cell autonomous neurodegeneration of amyotrophic lateral sclerosis (ALS). C-boutons, the large cholinergic synapses that innervate spinal α-motor neurons to control their excitability, are progressively lost from motor neurons in both human ALS and mutant Cu/Zn superoxide dismutase 1 (SOD1)-ALS mice. Neuregulin-1 (NRG1), a trophic factor implicated in neural development, transmission, and synaptic plasticity, has been reported to localize in the synapse of C-boutons. However, the roles of NRG1 in maintenance of motor neuron health and activity, as well as the functional consequences of its alteration in motor neuron disease, are not fully understood.

RESULTS: NRG1 was localized to the post-synaptic face of C-boutons and its expression was significantly lost in SOD1-ALS mice and human ALS patients. Losses of NRG1 expression and C-boutons occurred almost contemporaneously in SOD1-ALS mice. In addition, expressions of ErbB3 and ErbB4, receptors for NRG1, were reduced in the motor neurons of SOD1-ALS mice. Furthermore, viral-mediated delivery of type III-NRG1 to the spinal cord restored the number of C-boutons and extended the survival time of SOD1-ALS mice.

CONCLUSIONS: These results suggest that maintenance of NRG1-ErbB4/3 axis by supplementation of NRG1 confers neuroprotection in motor neuron disease, partly through the maintenance of C-boutons of spinal motor neurons.

Original languageEnglish
Pages (from-to)15
Number of pages1
JournalActa neuropathologica communications
Volume4
DOIs
Publication statusPublished - 2016 Feb 18

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Neuregulin-1
Amyotrophic Lateral Sclerosis
Motor Neurons
Motor Neuron Disease
Maintenance
Synapses
Neuronal Plasticity
Superoxide Dismutase-1
Neuroprotection
Interneurons
Synaptic Transmission
Neuroglia
Cholinergic Agents
Spinal Cord
Motor Activity
Survival

ASJC Scopus subject areas

  • Medicine(all)

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Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons. / Lasiene, Jurate; Komine, Okiru; Fujimori-Tonou, Noriko; Powers, Berit; Endo, Fumito; Watanabe, Seiji; Shijie, Jin; Ravits, John; Horner, Philip; Misawa, Hidemi; Yamanaka, Koji.

In: Acta neuropathologica communications, Vol. 4, 18.02.2016, p. 15.

Research output: Contribution to journalArticle

Lasiene, Jurate ; Komine, Okiru ; Fujimori-Tonou, Noriko ; Powers, Berit ; Endo, Fumito ; Watanabe, Seiji ; Shijie, Jin ; Ravits, John ; Horner, Philip ; Misawa, Hidemi ; Yamanaka, Koji. / Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons. In: Acta neuropathologica communications. 2016 ; Vol. 4. pp. 15.
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T1 - Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons

AU - Lasiene, Jurate

AU - Komine, Okiru

AU - Fujimori-Tonou, Noriko

AU - Powers, Berit

AU - Endo, Fumito

AU - Watanabe, Seiji

AU - Shijie, Jin

AU - Ravits, John

AU - Horner, Philip

AU - Misawa, Hidemi

AU - Yamanaka, Koji

PY - 2016/2/18

Y1 - 2016/2/18

N2 - INTRODUCTION: Increasing evidence implicates the role of the cell types surrounding motor neurons, such as interneurons and glial cells, in non-cell autonomous neurodegeneration of amyotrophic lateral sclerosis (ALS). C-boutons, the large cholinergic synapses that innervate spinal α-motor neurons to control their excitability, are progressively lost from motor neurons in both human ALS and mutant Cu/Zn superoxide dismutase 1 (SOD1)-ALS mice. Neuregulin-1 (NRG1), a trophic factor implicated in neural development, transmission, and synaptic plasticity, has been reported to localize in the synapse of C-boutons. However, the roles of NRG1 in maintenance of motor neuron health and activity, as well as the functional consequences of its alteration in motor neuron disease, are not fully understood.RESULTS: NRG1 was localized to the post-synaptic face of C-boutons and its expression was significantly lost in SOD1-ALS mice and human ALS patients. Losses of NRG1 expression and C-boutons occurred almost contemporaneously in SOD1-ALS mice. In addition, expressions of ErbB3 and ErbB4, receptors for NRG1, were reduced in the motor neurons of SOD1-ALS mice. Furthermore, viral-mediated delivery of type III-NRG1 to the spinal cord restored the number of C-boutons and extended the survival time of SOD1-ALS mice.CONCLUSIONS: These results suggest that maintenance of NRG1-ErbB4/3 axis by supplementation of NRG1 confers neuroprotection in motor neuron disease, partly through the maintenance of C-boutons of spinal motor neurons.

AB - INTRODUCTION: Increasing evidence implicates the role of the cell types surrounding motor neurons, such as interneurons and glial cells, in non-cell autonomous neurodegeneration of amyotrophic lateral sclerosis (ALS). C-boutons, the large cholinergic synapses that innervate spinal α-motor neurons to control their excitability, are progressively lost from motor neurons in both human ALS and mutant Cu/Zn superoxide dismutase 1 (SOD1)-ALS mice. Neuregulin-1 (NRG1), a trophic factor implicated in neural development, transmission, and synaptic plasticity, has been reported to localize in the synapse of C-boutons. However, the roles of NRG1 in maintenance of motor neuron health and activity, as well as the functional consequences of its alteration in motor neuron disease, are not fully understood.RESULTS: NRG1 was localized to the post-synaptic face of C-boutons and its expression was significantly lost in SOD1-ALS mice and human ALS patients. Losses of NRG1 expression and C-boutons occurred almost contemporaneously in SOD1-ALS mice. In addition, expressions of ErbB3 and ErbB4, receptors for NRG1, were reduced in the motor neurons of SOD1-ALS mice. Furthermore, viral-mediated delivery of type III-NRG1 to the spinal cord restored the number of C-boutons and extended the survival time of SOD1-ALS mice.CONCLUSIONS: These results suggest that maintenance of NRG1-ErbB4/3 axis by supplementation of NRG1 confers neuroprotection in motor neuron disease, partly through the maintenance of C-boutons of spinal motor neurons.

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