Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.

doi:10.1172/jci.insight.188459

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Article

Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.

JCI insight - 22 Aug 2025

Lin Karin, Ly Nina, Kunjamma Rejani B, Vu Ngoc, King Bryan, Robb Holly M, Mohler Eric G, Sridar Janani, Hao Qi, Zavala-Solorio José, Zhang Chunlian, Shahryari Varahram, van Bruggen Nick, Connelly Caitlin F, Bennett Bryson D, Lee James J, Sidrauski Carmela

Abstract excerpt

Maladaptive integrated stress response (ISR) activation is observed in human diseases of the brain. Genetic mutations of eIF2B, a critical mediator of protein synthesis, cause chronic pathway activation resulting in a leukodystrophy, but the precise mechanism is unknown. We generated N208Y eIF2B-α mice and found that this metabolite binding mutation led to destabilization of eIF2B-α, a systemic ISR, and neonatal...

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Topics

Animals
Mice
Cholesterol
Eukaryotic Initiation Factor-2B
Leukoencephalopathies

Methodology Data sources Editorial policy Privacy Delete account & data About Contact Helena Bioinformatics

Disease Models, Animal

Humans

Oligodendroglia

Stress, Physiological

Mutation

White Matter

Astrocytes

Male

Brain

Source

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Identifiers

PMID: 40674686
DOI: 10.1172/jci.insight.188459
PMCID: PMC12406721

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