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

Matthew S Elitt,Paul J Tesar,Zachary S Nevin,Lilianne Barbar,Mayur Madhavan,Daniel C Factor,Benjamin L.L Clayton,Kevin C Allan,Drew J Adams,Chen Weng,H Elizabeth Shick,Tyler E Miller,Baraa S Nawash,Angela M Lager,Fulai Jin,Yan Li

doi:10.1016/j.stemcr.2018.07.015

Abstract

SummaryPelizaeus-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.

Highlights

Leukodystophies are a class of rare, heritable disorders characterized by a loss of central nervous system (CNS) myelin
We directed all induced pluripotent stem cell (iPSC)-derived jimpy and wildtype control oligodendrocyte progenitor cells (OPCs) lines toward an oligodendrocyte fate (Figure 1A) and noted a striking absence of MBP+ oligodendrocytes in all jimpy lines (Figure 1B)
Jimpy OPCs showed increased propensity to acquire the late OPC/ immature oligodendrocyte marker O4 early in the differentiation process (Figures 1D and 1F), which may reflect a feedback loop to promote stem cell exit in the context of severe cell loss during oligodendrocyte differentiation. Together these results precisely define an early developmental susceptibility period during which transitioning jimpy OPCs die as they exit their progenitor cell state

Summary

Introduction

Leukodystophies are a class of rare, heritable disorders characterized by a loss of central nervous system (CNS) myelin These diseases impact approximately 1 in 7,500 live births, and are typified by extensive neurological impairment with reduced life expectancy (Bonkowsky et al, 2010; Parikh et al, 2015). While the disease is thought to be mediated through mutant PLP-induced endoplasmic reticulum (ER) stress (Garbern, 2007), complete appreciation of the cellular and molecular pathology in PMD remains elusive, in part due to complexities in accessing or appropriately modeling the disease-affected oligodendrocyte lineage during critical developmental windows (Bradl et al, 1999; Cerghet et al, 2001; Duncan et al, 2011; Gow et al, 1998; Knapp et al, 1986, 1987; Southwood et al, 2002; Williams and Gard, 1997).

Results

Discussion

Conclusion