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

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

doi:10.1186/s40478-016-0286-7

Abstract

IntroductionIncreasing 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.ResultsNRG1 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 occured 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0286-7) contains supplementary material, which is available to authorized users.

Highlights

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)
NRG1 was localized to the post-synaptic face of C-boutons and its expression was significantly lost in superoxide dismutase 1 (SOD1)-ALS mice and human ALS patients
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

Summary

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. In amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease, motor neurons are affected during the degenerative process. C-boutons are large cholinergic terminals that synapse onto spinal α-motor neurons, which are highly vulnerable in ALS. The origin of C-boutons was recently identified as partition cells, cholinergic interneurons located vicinity of the spinal central canal, and their role uncovered as critical modulators of motor neuron activity during locomotor behavior [5,6,7].

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