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

Autor: Francesca Pieropan, Filippo Calzolari, Andrea Rivera, Kasum Azim, Gareth Williams, Arthur M. Butt
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Myelin
Mice
Myelin Sheath
NSC
Neural stem cell
Systems Biology
OPC
Oligodendrocyte progenitor cell
High-Throughput Nucleotide Sequencing
LINCS
The Library of Integrated Network-based Cellular Signatures
Cell Differentiation
General Medicine
CNS
Central Nervous System
Oligodendroglia
medicine.anatomical_structure
Oligodendrogenesis
NFOL
Newly formed oligodendrocyte
OL
Oligodendrocyte
Signal Transduction
Subventricular zone
Optic nerve
In silico
Systems biology
Morpholines
SVZ
subventricular zone
Context (language use)
RM1-950
Biology
Article
medicine
Pharmacogenomics
The Library of Integrated Network-Based Cellular Signatures/LINCS
Animals
H-LY29
High concentration of LY294002
Computer Simulation
PI3K/AKT/mTOR pathway
L-LY29
Low concentration of LY294002
Pharmacology
PI3K/Akt
TCN
Triciribine
Dose-Response Relationship
Drug
Regeneration (biology)
Multiple sclerosis
medicine.disease
Oligodendrocyte
iNSCs
iPSC-derived NSCs
TAPs
Transiently amplifying progenitors
Mice
Inbred C57BL
MS
Multiple Sclerosis
iPCS
induced Pluripotent Stem Cell
Chromones
Pharmacogenetics
Therapeutics. Pharmacology
MOL
Myelinating oligodendrocyte
Neuroscience
Zdroj: Biomedicine & Pharmacotherapy, Vol 145, Iss, Pp 112436-(2022)
Biomedicine & Pharmacotherapy
ISSN: 0753-3322
Popis: 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.
Graphical Abstract ga1
Databáze: OpenAIRE
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