Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that pr...

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Autores principales:	A.D. Rivera, F. Pieropan, G. Williams, F. Calzolari, A.M. Butt, K. Azim
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Oligodendrogenesis Oligodendrocyte Pharmacogenomics, The Library of Integrated Network-Based Cellular Signatures/LINCS Subventricular zone Optic nerve PI3K/Akt Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/9c39d9c18650411aa069869eba42e464
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spelling	oai:doaj.org-article:9c39d9c18650411aa069869eba42e4642021-11-22T04:17:41ZDrug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination0753-332210.1016/j.biopha.2021.112436https://doaj.org/article/9c39d9c18650411aa069869eba42e4642022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012221https://doaj.org/toc/0753-3322Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.A.D. RiveraF. PieropanG. WilliamsF. CalzolariA.M. ButtK. AzimElsevierarticleOligodendrogenesisOligodendrocytePharmacogenomics, The Library of Integrated Network-Based Cellular Signatures/LINCSSubventricular zoneOptic nervePI3K/AktTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112436- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Oligodendrogenesis Oligodendrocyte Pharmacogenomics, The Library of Integrated Network-Based Cellular Signatures/LINCS Subventricular zone Optic nerve PI3K/Akt Therapeutics. Pharmacology RM1-950
spellingShingle	Oligodendrogenesis Oligodendrocyte Pharmacogenomics, The Library of Integrated Network-Based Cellular Signatures/LINCS Subventricular zone Optic nerve PI3K/Akt Therapeutics. Pharmacology RM1-950 A.D. Rivera F. Pieropan G. Williams F. Calzolari A.M. Butt K. Azim Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
description	Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.
format	article
author	A.D. Rivera F. Pieropan G. Williams F. Calzolari A.M. Butt K. Azim
author_facet	A.D. Rivera F. Pieropan G. Williams F. Calzolari A.M. Butt K. Azim
author_sort	A.D. Rivera
title	Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
title_short	Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
title_full	Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
title_fullStr	Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
title_full_unstemmed	Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
title_sort	drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/9c39d9c18650411aa069869eba42e464
work_keys_str_mv	AT adrivera drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination AT fpieropan drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination AT gwilliams drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination AT fcalzolari drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination AT ambutt drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination AT kazim drugconnectivitymappingandfunctionalanalysisrevealtherapeuticsmallmoleculesthatdifferentiallymodulatemyelination
_version_	1718418238947196928

Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination

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