Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Abstract

Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

Genotype-phenotype Correlation in Pelizaeus Merzbacher Disease and Pelizaeus Merzbacher-like Disease

“…OR duplications, on the other hand, had a moderate clinical severity and progression was not severe and these patients had milder ataxia and hypotonia even in late stages of the disease. In patients with X-linked deletion mutation, clinical findings were milder and progression rate was slower compared with other causative mutations, similar to previous publications (19). Clinical findings both in early and late stages of the disease were severe in patients with X-linked missense mutations, as previously reported (13).…”

Stem cell derived oligodendrocytes to study myelin diseases

“…iPSC derived OL In vitro (Nevin et al, 2017) PMD: Point mutation in PLP1 gene leads to reduced generation of oligodendrocytes and protein mislocalization associated with ER stress. PLP1 duplication and deletion results in reduced and normal derivation of oligodendrocytes, respectively.…”

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

“…This indicates an increased number of immature premyelinating OPCs, and therefore primary oligodendrocyte pathology cannot be excluded (Bugiani et al, 2011). As the human induced pluripotent stem cell (iPSC) technology is increasingly advancing, disease‐modelling studies could identify vulnerable glial cell types in VWM (Nevin et al, 2017). Secondly, the generation of transplantable cells that are safe and are not rejected by the patient is challenging.…”