Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice
Abstract Nogo–Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs),...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-12-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01758-7 |
| _version_ | 1797388544377880576 |
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| author | Takuya Ikeda Keita Takahashi Minatsu Higashi Hiroyasu Komiya Tetsuya Asano Akihiro Ogasawara Shun Kubota Shunta Hashiguchi Misako Kunii Kenichi Tanaka Mikiko Tada Hiroshi Doi Hideyuki Takeuchi Kohtaro Takei Fumiaki Tanaka |
| author_facet | Takuya Ikeda Keita Takahashi Minatsu Higashi Hiroyasu Komiya Tetsuya Asano Akihiro Ogasawara Shun Kubota Shunta Hashiguchi Misako Kunii Kenichi Tanaka Mikiko Tada Hiroshi Doi Hideyuki Takeuchi Kohtaro Takei Fumiaki Tanaka |
| author_sort | Takuya Ikeda |
| collection | DOAJ |
| description | Abstract Nogo–Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS. |
| first_indexed | 2024-03-08T22:41:21Z |
| format | Article |
| id | doaj.art-6bc952e6666947de89b52f8fcf5a7f1c |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-08T22:41:21Z |
| publishDate | 2023-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-6bc952e6666947de89b52f8fcf5a7f1c2023-12-17T12:07:02ZengNature Publishing GroupCell Death Discovery2058-77162023-12-019111010.1038/s41420-023-01758-7Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model miceTakuya Ikeda0Keita Takahashi1Minatsu Higashi2Hiroyasu Komiya3Tetsuya Asano4Akihiro Ogasawara5Shun Kubota6Shunta Hashiguchi7Misako Kunii8Kenichi Tanaka9Mikiko Tada10Hiroshi Doi11Hideyuki Takeuchi12Kohtaro Takei13Fumiaki Tanaka14Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineMolecular Medical Bioscience Laboratory, Yokohama City University Graduate School of Medical Life ScienceDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of MedicineAbstract Nogo–Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.https://doi.org/10.1038/s41420-023-01758-7 |
| spellingShingle | Takuya Ikeda Keita Takahashi Minatsu Higashi Hiroyasu Komiya Tetsuya Asano Akihiro Ogasawara Shun Kubota Shunta Hashiguchi Misako Kunii Kenichi Tanaka Mikiko Tada Hiroshi Doi Hideyuki Takeuchi Kohtaro Takei Fumiaki Tanaka Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice Cell Death Discovery |
| title | Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| title_full | Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| title_fullStr | Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| title_full_unstemmed | Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| title_short | Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| title_sort | lateral olfactory tract usher substance lotus an endogenous nogo receptor antagonist ameliorates disease progression in amyotrophic lateral sclerosis model mice |
| url | https://doi.org/10.1038/s41420-023-01758-7 |
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