Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease

Stem Cell Reports
Matthew S ElittPaul J Tesar

Abstract

Pelizaeus-Merzbacher disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1jimpy. Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25-6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.

Citations

Jul 2, 2020·Nature·Matthew S ElittPaul J Tesar
Oct 23, 2019·Neural Regeneration Research·Wensheng Lin, Sarrabeth Stone
Aug 15, 2020·Frontiers in Molecular Biosciences·Anne E J Hillen, Vivi M Heine
Oct 23, 2020·Cell Stem Cell·Kevin C AllanPaul J Tesar
Dec 17, 2020·Nature Reviews. Neurology·Nicole I WolfMarjo S van der Knaap
Dec 10, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Monica R LangleyIsobel A Scarisbrick
Mar 26, 2021·Frontiers in Cell and Developmental Biology·Greg J DuncanBen Emery
Apr 6, 2021·Frontiers in Cellular Neuroscience·Mohammed R ShakerErnst J Wolvetang

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Methods Mentioned

BETA
Dissection
scRNA-Seq
RNA-seq
Assay

Software Mentioned

Jimpy
Acapella
Drop
GSEA
Operetta High Content Imaging and Analysis system
Adobe Photoshop
Operetta
Seq
Harmony
GraphPad Prism

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