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

ABSTRACT: Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease [RNA-seq]

PROVIDER: PRJNA437485 | ENA |

REPOSITORIES: ENA

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

Project description: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 iPSC-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.

2018-08-22 | GSE111595 | GEO

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

2018-08-22 | GSE111599 | GEO

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

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

| PRJNA437490 | ENA

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

Project description:Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease [scRNA-seq]

| PRJNA437536 | ENA

Chemical chaperone screening for Pelizaeus-Merzbacher disease

Project description:Chemical chaperone screening for Pelizaeus-Merzbacher disease

| PRJNA510573 | ENA

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

Project description: Not available

| S-EPMC6135742 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-08-22 | GSE111605 | GEO

Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication

Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals M-bM-^@M-^S 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homologyM-bM-^@M-^Tor homeologyM-bM-^@M-^Tdriven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model. To determine size, genomic extent and gene content for each rearrangement, we used a customized tiling-path oligonucleotide microarray spanning the Xq22 chromosomal region to query the genomic DNA of 7 males with Pelizaeus-Merzbacher disease, and 5 unaffected or carrier/unaffected family members. A 4x44k Agilent Technologies (Santa Clara, CA) microarray was designed using the Agilent e-array website targeting the region of the genome encompassing the dosage-sensitive PLP1 gene.

2014-11-25 | E-GEOD-63594 | biostudies-arrayexpress

Mus musculus

Project description:Progesterone Antagonist Therapy in a Pelizaeus-Merzbacher Mouse Mode

| PRJNA239308 | ENA

Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43

Project description:We performed bulk RNA-seq on FACS-isolated oligodendrocytes from P30 Mobp-TDP43 and Mog-TDP43 mouse lines to determine the effect of TDP-43 loss at different stages of oligodendrocyte development.

2022-01-03 | GSE188903 | GEO

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