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Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1G93A Mice Models Uncover Potential Drug Treatments for ALS

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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 SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A 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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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Medeniyet University, Kuzey Yerleşkesi H Blok, Ünalan Sk. D100 Karayolu Yanyol 34700, Istanbul, Turkey

    Elif Kubat Oktem

  2. Department of Bioengineering, Faculty of Engineering and Architecture, Konya Food and Agriculture University, Konya, Turkey

    Busra Aydin

  3. Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul, Turkey

    Metin Yazar

  4. Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey

    Metin Yazar & Kazim Yalcin Arga

  5. Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey

    Kazim Yalcin Arga

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EKO conceived the original idea, conceptualized the study, performed analysis, prepared figures and tables, and wrote the manuscript. BA performed analysis, prepared figures and tables, and wrote the manuscript. MY performed analysis and prepared figures and tables. KYA conceptualized the study, supervised the study and improved the final version of the manuscript. All authors reviewed and approved the final version of the manuscript.

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Kubat Oktem, E., Aydin, B., Yazar, M. et al. Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1G93A Mice Models Uncover Potential Drug Treatments for ALS. J Mol Neurosci 72, 2360–2376 (2022). https://doi.org/10.1007/s12031-022-02071-1

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