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

Summary: 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. : Tesar and colleagues interrogate the severe genetic myelin disorder Pelizaeus-Merzbacher disease (PMD) using iPSC-derived oligodendrocyte progenitor cells (OPCs). Using high-throughput phenotypic screening, they rescue cell death of mutant oligodendrocytes immediately after initiation of differentiation with chemical modulators, including Ro 25–6981. Interestingly oligodendrocyte restoration did not lead to widespread myelination, unmasking a new phase of the disease. Keywords: iPSC disease modeling, high-throughput screening, oligodendrocyte progenitor cells, oligodendrocytes, myelin, Pelizaeus-Merzbacher disease, proteolipid protein 1, endoplasmic reticulum stress, PLP1, rare disease