Abstract
The leukodystrophy Pelizaeus-Merzbacher disease (PMD) is caused by myelin protein proteolipid protein gene (PLP1) mutations. PMD is characterized by oligodendrocyte death and CNS hypomyelination; thus, increasing oligodendrocyte survival and enhancing myelination could provide therapeutic benefit. Here, we use the PMD mouse model Jimpy to determine the impact of the integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression. Male Jimpy animals in which the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase, protein kinase-like endoplasmic reticulum kinase (PERK), is inactivated have an extended lifespan that correlates with increased oligodendrocyte survival and enhanced CNS myelination. Inactivation of downstream components of the ISR pathway, in contrast, does not rescue oligodendrocytes or myelin. Phosphorylated eIF2α inhibits the exchange factor eIF2B, resulting in diminished protein synthesis. Treatment with small molecule eIF2B activators 2BAct and ISRIB increases oligodendrocyte survival, CNS myelination, and doubled the Jimpy lifespan. These results suggest that ISR modulation could provide therapeutic benefit to PMD patients.
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Source data are provided with this paper. The RNA-seq raw data of mice generated in this study can be accessed at the National Center for Biotechnology Information Gene Expression Omnibus (GEO) under the access code GSE277705. Source data are provided with this paper.
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Acknowledgements
We would like to thank Paul Tesar, David Ron, Doug Cavener and David Rowitch for generously providing mouse strains used in the study. We would like to thank Ani Solanki (University of Chicago), Erdong Liu (Northwestern University), Samatha Wills, Alvin Chapagai, Taha Gabr, and Metin Aksu (Loyola University Chicago) for technical support. This research was supported by NIH grants 5R01NS034939 and 1R35NS137478 to B.P. B.P. and D.E.B. are supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and B.P. receives funding from the Rampy MS Research Foundation. Y.C. is the recipient of a National Multiple Sclerosis Society Career Transition Fellowship TA-2008-37043. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.
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Y.C., R.K., L.K., M.D., K.B., I.S., Y.H.C., J.C.Z., J.E.V.B., S.E., and G.N. performed the experiment. K.L. and C.C. analyzed the RNAseq data. Y.C., R.K., D.B., C.S., and B.P. planned the study. Y.C. and B.P. wrote the manuscript with substantial contribution from R.K., K.L., J.E.V.B., D.B., and C.S.
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Brian Popko is on the scientific advisory board of InFlectis Biosciences, which has an interest in modulating the ISR for neurodegenerative disorders. There is no conflict with the current study. Rejani B. Kunjamma, Karin Lin, and Caitlin F. Connelly (at time of contribution) are employees of Calico Life Sciences LLC and have no additional financial interests to declare. Carmela Sidrauski is an employee of Calico Life Sciences LLC and is listed as an inventor on a patent application WO2017193063 describing 2BAct. 2BAct was used in this study to treat Jimpy mice. This composition of matter patent covering 2BAct and related analogs has been published. The remaining authors declare no competing interests.
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Chen, Y., Kunjamma, R.B., Lin, K. et al. Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival. Nat Commun (2025). https://doi.org/10.1038/s41467-025-68045-0
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DOI: https://doi.org/10.1038/s41467-025-68045-0
