Integrative Analysis of Motor Neuron and Microglial Transcriptomes from $ SOD1^{G93A} $ Mice Models Uncover Potential Drug Treatments for ALS
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage $ SOD1^{G93A} $ microglia and age-matched $ SOD1^{G93A} $ motor neurons are poorly understood. We evaluated the differential gene expression profiles in $ SOD1^{G93A} $ microglia and $ SOD1^{G93A} $ motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:72 |
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| Enthalten in: |
Journal of molecular neuroscience - 72(2022), 11 vom: 30. Sept., Seite 2360-2376 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kubat Oktem, Elif [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Amyotrophic lateral sclerosis |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s12031-022-02071-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage $ SOD1^{G93A} $ microglia and age-matched $ SOD1^{G93A} $ motor neurons are poorly understood. We evaluated the differential gene expression profiles in $ SOD1^{G93A} $ microglia and $ SOD1^{G93A} $ motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning. | ||
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