Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1<SUP>G93A</SUP> Mice Models Uncover Potential Drug Treatments for ALS
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Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
Springernature
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.
Description
Keywords
SOD1 mutation, Amyotrophic lateral sclerosis, Transcriptomic, Drug repositioning, Repositioned therapeutics
Turkish CoHE Thesis Center URL
Citation
5
WoS Q
Q3
Scopus Q
Q2
Source
Volume
72
Issue
11
Start Page
2360
End Page
2376