Motor neuron heterogeneity and selective vulnerability in ALS
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- Misawa Hidemi
- Division of Pharmacology, Faculty of Pharmacy, Keio University
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- Morisaki Yuta
- Division of Pharmacology, Faculty of Pharmacy, Keio University
Bibliographic Information
- Other Title
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- 運動ニューロンサブタイプとALSにおける選択的脆弱性の解析
- ウンドウ ニューロンサブタイプ ト ALS ニ オケル センタクテキ ゼイジャクセイ ノ カイセキ
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Abstract
<p>Different and selective vulnerability among motor neuron subtypes are a fundamental, but unexplained, feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) motor neurons are the most vulnerable, and fast fatigue-resistant/slow (FR/S) motor neurons are relatively resistant. We identified that osteopontin (OPN) can serve as a marker of FR/S motor neurons, whereas matrix metalloproteinase-9 (MMP9) is expressed by FF motor neurons in mice. In SOD1G93A ALS model mice, as the disease progressed, OPN was secreted and accumulated as granular deposits in the extracellular matrix. We also detected OPN/MMP9 co-expressed motor neurons around the disease onset. These double positive motor neurons showed the expression of αvβ3 integrin (OPN receptor) and up-regulation of ER stress markers. We discovered that the double positive motor neurons are remodeled FR/S motor neurons, which compensated for FF motor neuron degeneration (the first wave of degeneration). Genetic ablation of OPN delayed the onset of disease, but later accelerated disease progression. This reflects two modes of OPN involvement in the pathogenesis of ALS: cell-autonomous and non-cell-autonomous effects on motor neuron vulnerability. Our study suggests that OPN expressed in FR/S motor neurons is involved in the second wave of motor neuron degeneration in ALS, and an OPN-αvβ3 integrin-MMP9 axis could be a potentially useful therapeutic target for ALS.</p>
Journal
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- Folia Pharmacologica Japonica
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Folia Pharmacologica Japonica 152 (2), 64-69, 2018
The Japanese Pharmacological Society
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Details 詳細情報について
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- CRID
- 1390001288054018944
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- NII Article ID
- 130007432674
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- NII Book ID
- AN00198335
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- ISSN
- 13478397
- 00155691
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- NDL BIB ID
- 029184816
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- PubMed
- 30101862
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- Text Lang
- ja
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed