Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons
- Jurate Lasiene†1,
- Okiru Komine†2,
- Noriko Fujimori-Tonou†1, 3,
- Berit Powers4, 5,
- Fumito Endo2,
- Seiji Watanabe2,
- Jin Shijie2,
- John Ravits6,
- Philip Horner4,
- Hidemi Misawa7 and
- Koji Yamanaka1, 2Email author
© Lasiene et al. 2016
Received: 10 February 2016
Accepted: 10 February 2016
Published: 18 February 2016
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.
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 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.
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.
KeywordsAmyotrophic lateral sclerosis Neuregulin 1 C-bouton SOD1 ErbB4
A key characteristic of neurodegenerative diseases is the degeneration of a specific type of neuron. In amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease, motor neurons are specifically affected during the degenerative process. While the majority of ALS cases are of sporadic etiology, approximately 10 % of cases are inherited, and dominant mutations in the gene for copper/zinc superoxide dismutase (SOD1) are a frequent cause of inherited ALS. Using transgenic rodent and fish models of SOD1-linked ALS that recapitulate specific motor neuron degeneration, the cell types surrounding motor neurons, including glial cells and interneurons, have been shown to be actively involved in ALS pathogenesis [1–4].
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 [5–7]. Intriguingly, C-boutons do not terminate on the cranial motor neurons innervating eye muscles, which are spared in ALS. In sporadic ALS patients, losses of C-boutons on spinal motor neurons remaining at autopsy were documented . However, alteration of C-boutons in symptomatic mutant SOD1 mice reported by several groups was variable: one report showed a significant loss of C-boutons , while the other groups reported moderate  or marginal [11, 12] loss of C-boutons. Moreover, the reports demonstrate early reduction of choline acetyltransferase (ChAT) at C-boutons in presymptomatic SOD1G93A mice  and reduced immunoreactivity for vesicular acetylcholine transporter (VAChT) in motor neurons in 80 day-old, presymptomatic SOD1G93A mice . Others demonstrate a decrease in VAChT-positive boutons following symptomatic onset in mouse models [9, 15]. These reports suggest that C-boutons could be linked to pathomechanism of ALS, however, existing evidence of altered numbers and roles of C-boutons in ALS patients and models is contradictory and largely inconclusive.
Neuregulin 1 (NRG1), is an epidermal growth factor (EGF)-like trophic factor implicated in neural development, synaptic transmission and plasticity, Schwann cell differentiation, and the regulation of myelin sheath thickness [16, 17]. NRG1 is localized to the cholinergic synapses (C-boutons) that innervate motor neuron somata and proximal processes  and modulate the activity of motor neurons. In addition to known involvement of NRG1 in schizophrenia , recent data suggests the possible involvement of NRG1 in ALS. A dominant mutation in the gene for ErbB4, encoding a receptor for NRG1, is causative for familial ALS type 19 . Moreover, although the results are not entirely consistent with each other, altered expression of NRG1 has been reported in the lesions of mutant SOD1 mice [9, 20]. These accumulating data suggest that NRG1 could participate in stabilizing synapses or in regulating activity of motor neurons at C-boutons and that its dysregulation could contribute to motor neuron degeneration in ALS. However, its localization in normal and diseased motor neurons and whether NRG1 has neuroprotective properties are not fully understood.
In this study, we found that NRG1 was localized in the post-synaptic face of C-boutons and its expression was significantly lost in SOD1-linked ALS mice and human ALS patients. Viral-mediated delivery of type III NRG1 restored the number of C-boutons and extended the survival time of SOD1G93A mice. These results suggest that NRG1 exerts neuroprotective properties in motor neuron disease partly through maintenance of C-boutons of spinal motor neurons.
Materials and Methods
Transgenic mouse lines and survival experiments
Transgenic mouse lines expressing human SOD1 gene with ALS-linked mutations, SOD1G93A [B6.Cg-Tg(SOD1*G93A)1Gur/J] or SOD1G85R [B6.Cg-Tg(SOD1*G85R)148Dwc/J] were obtained from Jackson laboratory or were gifts from Dr. Don Cleveland (University of California, San Diego). Onset and survival times for mutant SOD1 mice are 100–105 and 150–160 days old for SOD1G93A mice, and 11–12 and 12–13 months old for SOD1G85R mice, respectively. Genotyping of SOD1 transgenic mice was identified by polymerase chain reaction (PCR) as previously described .
All animal procedures were conducted in accordance with the guidelines of the Animal Use and Care Committees of Nagoya University, Keio University and RIKEN. Transgenic animals are always compared with their non-transgenic littermates to minimize the effects of different genetic background. Times of disease onset and end stage were determined respectively as the time when mice had started losing the maximum body weight and when animals failed in righting themselves within 20 s when placed on their backs, an endpoint commonly used for mutant SOD1 expressing mice which is compliant with the requirements of the Animal Use and Care Committee. Statistical analysis of onset and survival time was performed with Gehan-Breslow-Wilcoxon test by using GraphPad Prism (GraphPad Software, USA).
Postmortem human tissues
Detail of the patients. The spinal cord specimens from three sporadic ALS and control patients with other diseases were analyzed. Disease controls include Parkinson’s diseases, cerebrovascular disease, and liver failure
Time of sampling after death (hrs)
Age at death
Site of Onset
Disease Course (yrs)
Respiratory & trunk
Basilar artery occlusion
Following primary antibodies were used in the study: anti-NRG1 (rabbit; 1:500, sc-348, Santa Cruz, USA), anti-VAChT (guinea pig; 1:250, AB1588, Merck Millipore, USA), anti-ChAT (goat; 1:100, AB144P, Merck Millipore), anti-NeuN (mouse; 1:1000, MAB377, Merck Millipore), anti-Kv2.1 (mouse; 1:250, clone K89/34, NeuroMab, USA), anti m2 muscarinic receptor (rat; 1:500, MAB367, Merck Millipore), anti-GFAP (mouse; 1:500, G3893, Sigma-Aldrich, USA), anti-Iba1 (rabbit; 1:500, 019-19741, Wako, Japan), anti-ErbB3 (rabbit; 1:50, sc-285, Santa Cruz), and anti-ErbB4 (mouse; 1:300, MS-270-P0, Thermo Fisher Scientific, USA).
Immunofluorescence was performed as described previously . For human spinal cords, 20 μm sections were made of fresh frozen tissue, air dried on slides, and fixed in ice-cold acetone for 10 min. In brief, after blocking for 1 h, the sections were incubated with primary antibodies overnight at 4 °C. Bound antibodies were detected with appropriate Alexa Fluor-conjugated anti-rabbit, mouse, rat, goat, or guinea pig IgG antibodies (Thermo Fisher Scientific). For detecting ErbB3 antibody, Cy3-conjugated anti-rabbit IgG antibody (Jackson Laboratories, USA) was used. Immunostained images were obtained by confocal laser scanning microscopy (LSM 5 Exciter, LSM-700; Carl Zeiss AG, Germany) and the equipped software (Zen; Carl Zeiss AG).
Quantification of NRG1, VAChT-immunopositive puncta and the size of motor neurons
Sections of mouse lumbar spinal cords were triple-immunostained with the antibodies for NRG1, VAChT, and NeuN and appropriate secondaries. After obtaining three-dimensional images of immunostained lumbar spinal cord sections of mice, 30 to 60 motor neurons from two to five animals per genotype were quantified for NRG1- and VAChT- immunoreactivity surrounding motor neurons. Lumbar motor neurons were positively identified as large, NeuN-positive neurons surrounded by VAChT-positive puncta located in the anterior horn. Quantified data were statistically analyzed with one-way ANOVA with Bonferroni’s Multiple Comparison test or Kruskal-Wallis test with Dunn’s Multiple Comparison test.
For human tissue, spinal cord sections were stained with the antibodies for NRG1 and ChAT. After obtaining three-dimensional images of immunostained spinal cord sections, a minimum of 15–20 motor neurons from each of 3 ALS patients at each spinal level (cervical, thoracic, and lumbar) were quantified for NRG1-positive puncta and compared to individuals who died of causes unrelated to ALS. Data was statistically analyzed by one-way ANOVA with Bonferroni correction.
To analyze the size of motor neurons, total of 60 lumbar motor neurons immunopositive for anti-ChAT or anti-NeuN antibody from three mice per each group was quantified for the surface area by using the Image J software.
Preparation and stereotaxic injection of recombinant adeno-associated virus (AAV) encoding NRG1
The adeno-associated viral expression constructs chimeric rAAV1/2-CAG-NRG1-IRES-EGFP-WPRE (woodchuck post-translational regulatory element) were constructed by subcloning Type I-NRG1 or Type III (SMDF)-NRG1 cDNA into the rAAV1/2 cassette. Viral vectors were packaged and purified at a high titer suitable for expression in mouse spinal cords (GeneDetect, New Zealand). The stereotaxic injections of rAAV into SOD1G93A mice were performed at 65 days old or 105 days old. The mice were anesthetized by intraperitoneal injection of pentobarbital, then 0.5 μl of rAAV was injected bilaterally into the lumbar ventral spinal cord at Th13, L1, and L2 levels of the spine for a total volume of 3 μl, equivalent to 3.6 × 108 viral particles. Similar quantities of rAAV-GFP were also injected into a control group of mice.
Reverse transcribed PCR
Total RNA was extracted from lumbar spinal cords using TRIzol (Thermo Fisher Scientific) and purified using an RNeasy Mini Kit (Qiagen, Valencia, USA). cDNA was synthesized from total RNA using PrimeScript II 1st strand cDNA Synthesis Kit (Takara Bio, Japan). Quantitative RT-PCR was performed using SYBR Premix Ex Taq II (Takara Bio) using gene specific primers as follows. Type III-NRG1: GAGGTGAGAACACCCAAGTCA, TGGTCCCAGTCGTGGATGTAG; Type I-NRG1: TGCCAACATCACCATTGTTGA, GGACACATAGGGTCTTTCAGTTGA . Primers for Type III-NRG1 were also used for semi-quantitative PCR.
Neuregulin 1 is localized to the post-synaptic face of C-bouton in mouse spinal motor neurons
Age-dependent loss of NRG1 in lumbar spinal motor neurons of SOD1G93A and SOD1G85R mice
Loss of NRG1-positive puncta in the spinal motor neurons of sporadic ALS patients
Viral-mediated delivery of type III NRG1 extends the survival time of SOD1G93A mice
Viral-mediated delivery of NRG1 restores the number of NRG1-positive puncta and increases the size of motor neuron somata in SOD1G93A mice
ErbB4 and ErbB3 expressions are reduced in SOD1G93A motor neurons
Recently, localization of NRG1 has been documented at cholinergic synapses that innervate spinal motor neurons, called C-boutons . Alterations in the numbers or sizes of C-boutons have been reported in ALS patients and mouse models [8–12, 26, 27]. This, together with the recent discovery that a mutation in ErbB4, a component of NRG1 receptors, is causative for ALS19 , suggests that disruption of the NRG1-ErbB4 axis could play a role in ALS neurodegeneration. In this study, we determined that NRG1 is enriched at the post-synaptic face of C-boutons in spinal motor neurons. We also found that expression of NRG1 was significantly lost in symptomatic ALS mice and human ALS, and that expressions of ErbB4 and ErbB3 are reduced in the motor neurons of ALS mice around the disease onset. Finally, we report that viral-mediated delivery of type III NRG1 restored the number of C-boutons and extended survival times of SOD1G93A mice. These results suggest that supplementation of NRG1 is capable of ameliorating motor neuron disease partly through maintenance of C-boutons of spinal motor neurons.
Using immunoreactivity of VAChT, alteration of C-boutons in mutant SOD1 mice reported by the several groups was inconclusive [9–12]. Our analyses revealed moderate loss of C-boutons in two distinct strains of symptomatic mutant SOD1 mice, SOD1G93A and SOD1G85R. Discrepancy among these previous studies may be attributed to a difference in methods and choice of motor neurons for quantification. Since moderate losses of C-boutons and NRG1 expression in motor neurons were observed almost contemporaneously, reduction of NRG1 in motor neurons may occur not through dysfunction of C-bouton mediated cholinergic inputs but through the general impairment of pre-degenerating motor neurons. In addition, although Song and colleague reported that type I NRG1 mRNA was elevated in end-stage SOD1G93A mice , we observed the levels of both type I and type III NRG1 mRNAs were reduced in the spinal cord of symptomatic SOD1G93A and SOD1G85R mice. Discrepancy between two studies might be partly attributed to the genetic background of SOD1G93A mice used in the study by Song and colleague. Future studies will reveal the detailed expression profiles of NRG1 splice variants in ALS mice.
Our detailed immunofluorescence study revealed that NRG1 immunoreactivity co-localized with the post-synaptic proteins, m2 muscarinic receptors and voltage-gated Kv2.1 channels, and not with the pre-synaptic protein, VAChT. These findings indicated that NRG1 was localized in the post-synaptic face of C-boutons, a finding similar to the one reported by Gallart-Palau et al . This indicates that the source of NRG1 expression is motor neurons themselves. In the nervous system, NRG1 plays multiple roles in neural development, synaptic plasticity and transmission, Schwann cell differentiation, and regulation of myelin sheath thickness [16, 17]. Although one group reported ErbB4 receptor is localized in presynaptic terminal of C-boutons , our staining revealed that ErbB4 is not co-localized with VAChT. Instead, ErbB4 immunoreactivity is mainly observed in motor neuron somata with punctate staining. Moreover, we observed for the first time that ErbB4 and ErbB3 expressions in motor neurons decreased just prior to the losses of NRG1/VAChT puncta in mutant SOD1 mice, despite that the mechanism of progressive loss of ErbB4/ErbB3 remains unclear. Progressive losses of ErbB4/B3 in the motor neurons may explain that neuroprotection was achieved by the administration of type III-NRG1 at the presymptomatic stage, not at the symptomatic stage.
Previous studies showed that the number of C-boutons per motor neuron was transiently increased in P8-P30 SOD1G93A mice [12, 27] and that C-boutons become enlarged in response to motor neuron damage, leading to increased excitability of motor neurons [12, 26]. These phenomena were interpreted as a compensatory mechanism to maintain the function of motor neurons. Our study partially supports this hypothesis, since viral-mediated supplementation of type III-NRG1 provided neuroprotection by increasing the number of C-boutons, rather than the size. On the other hand, our immunostaining revealed that ErbB4 receptor was mainly localized to the motor neuron membrane rather than to partition cells, while ErbB3 expressed in the all spinal neurons including the partition cells. Considering that NRG1 and ErbB4 are selectively localized to the motor neurons in the spinal cord, we propose that NRG1 may provide neuroprotection to motor neurons directly through ErbB4 receptors in motor neuron somata. In many cases, NRG1-ErbB signaling is observed at the synaptic terminal, the interface of nerve axon and Schwann cells, or neuromuscular junction . However, autocrine signaling of NRG1-ErbB is observed in Schwann cell differentiation and remyelination or tumor growth [28–30]. In addition, NRG1 is known to exert neuroprotection through ErbB4 receptor in MPTP models of Parkinson’s disease  and cerebral ischemia . Therefore, NRG1 may protect motor neurons through ErbB4 by an autocrine fashion.
Alternatively, it is possible that NRG1 confers neuroprotection indirectly via ErbB3 in the partition cells or their neighboring astrocytes and oligodendrocytes to maintain the number and integrity of C-boutons. Several reports have described the roles of interneurons in SOD1-ALS models. Glycinergic interneurons are degenerated prior to symptomatic onset in SOD1G93A mice, while no significant change in other interneurons, such as GABAergic neurons was found . Although only modest degrees of changes in cholinergic interneurons has been reported, including herein, further examination of the role of interneurons in non-cell autonomous aspects of motor neurodegeneration will provide a more complete picture of pathomechanisms in ALS.
Our study is the first to demonstrate dysregulation of the NRG1-ErbB4/3 axis in both human and mouse ALS and to provide support for NRG1 supplementation as a possible therapeutic option for motor neuron disease. Considering that NRG1 conferred increased survival in SOD1-ALS mice and its receptors ErbB4/3 were dysregulated, maintenance of the NRG1-ErbB4/3 axis might be crucial for mitigation of SOD1-ALS. Lastly, since NRG1 was also lost in sporadic ALS motor neurons, it may also play a role in motor neuron health in non-SOD1 associated ALS.
amyotrophic lateral sclerosis
glial fibrillary acidic protein
M2 muscarinic acetylcholine receptor
polymerase chain reaction
copper/zinc superoxide dismutase-1
vesicular acetylcholine transporter
woodchuck post-translational regulatory element
The authors thank the Support Unit for Animal Resource Development in RIKEN BSI Research Resources Center for supporting animal experiments.
This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (23111006: to K.Y.) and Scientific Research (B) (26293208: to K.Y.), Grants-in-Aid for Young Scientists (B) (26830046: to O.K.), for JSPS fellows (10 F00518: to J.L.) from the Ministry for Education, Culture, and Sports, Science and Technology of Japan, Grant-in-Aid for Research on rare and intractable diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis, from Japan Agency for Medical Research and Development (AMED), Daiko Foundation, Uehara Memorial Foundation, and IBC grant from Japan ALS association (K.Y.). J.L. is supported by JSPS postdoctoral fellowship for foreign researchers.
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