Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1 G93A Mice Models Uncover Potential Drug Treatments for ALS.

Autor: Kubat Oktem E; 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. ekoktem@outlook.com., Aydin B; Department of Bioengineering, Faculty of Engineering and Architecture, Konya Food and Agriculture University, Konya, Turkey., Yazar M; Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul, Turkey.; Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey., Arga KY; Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.; Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey.
Jazyk: angličtina
Zdroj: Journal of molecular neuroscience : MN [J Mol Neurosci] 2022 Nov; Vol. 72 (11), pp. 2360-2376. Date of Electronic Publication: 2022 Sep 30.
DOI: 10.1007/s12031-022-02071-1
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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