JANTRAPIROM, S. O. | bioRxiv Science

bioRxiv2026

A leukemia-derived ENL/AF9 chemical probe enhances neuronal stress resilience and ameliorates ALS phenotypes

Chemical perturbation of chromatin reader proteins provides a precise strategy to interrogate epigenetic control of neuronal stress adaptation. ENL and AF9 are YEATS-domain acyl-lysine readers best characterized in leukemia, but their roles in neurons remain unclear. Here, we use the selective YEATS inhibitor SR-0813 to define ENL/AF9 function in neuronal stress responses across Drosophila and human systems. SR-0813 phenocopies genetic ENL/AF9 reduction by extending lifespan and enhancing stress tolerance in vivo, and improves survival of human neurons under multiple stress conditions, with the strongest effects during endoplasmic reticulum stress. Mechanistically, SR-0813 attenuates PERK-ISR signaling and reduces apoptotic commitment without broadly enhancing proteostasis capacity. Notably, its effects are highly context dependent, conferring protection in stress-signaling-driven models but reduced efficacy or detrimental outcomes under chronic aggregation or mitochondrial stress. These findings identify ENL/AF9 as modulators of stress-response dynamics and highlight YEATS-domain inhibition as a context-dependent strategy to reshape neuronal resilience. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/717610v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@e7bee4org.highwire.dtl.DTLVardef@a59d76org.highwire.dtl.DTLVardef@104dd7eorg.highwire.dtl.DTLVardef@69bb51_HPS_FORMAT_FIGEXP M_FIG C_FIG siRNA or the YEATS-domain inhibitor SR-0813 suppress the acyl-lysine reader ENL/AF9, extending lifespan and increasing H2O2 tolerance in Drosophila. In neurons (Drosophila and SH-SY5Y), ENL/AF9 inhibition lowers PERK-ISR signaling and apoptosis while maintaining proteostasis. Effects are context dependent: protective under UPR/ISR-dominant stress but potentially detrimental under aggregation or mitochondrial stress. Created with BioRender.

cell biology↗

bioRxiv2025

Diesel exhaust particles induce lasting and age-dependent damage to the brain in Drosophila melanogaster

Diesel exhaust particles (DEP), major air pollutants emitted from automobile engines, contain numerous toxic compounds. While the adverse effects of DEP exposure on the respiratory and cardiovascular systems are well documented, its impact on brain health remains poorly understood. In this study, we employed Drosophila melanogaster as a model organism to investigate the neurological effects of DEP exposure and the impact of exposure cessation across different age groups. Molecular, histopathological, and behavioral markers were assessed before and after exposure to varying doses of DEP at different time intervals.Interestingly, DEP exposure induced age-dependent cellular responses in the brain, including elevated reactive oxygen species (ROS), increased neuroinflammation, and disruption of the blood-brain barrier (BBB). Prolonged exposure led to pronounced vacuolization in the brains of aged flies. While cessation of DEP exposure resulted in partial recovery in young flies particularly when implemented early, aged flies exhibited limited benefit, with persistent evidence of likely irreversible brain damage. Overall, this study invites greater public awareness and careful consideration in public health policy to limit long-term DEP exposure, particularly among older individuals, and to encourage strategies that reduce potential risks to brain health associated with air pollution. Highlights1) DEP exposure is detrimental to the brain. 2) The brain responds to DEP exposure in an age-specific manner. 3) Permanent damage to the brain of old flies results from DEP exposure. 4) Cessation mitigates DEP-induced brain impairments when implemented at a young age. Environmental ImplicationOur study highlights the detrimental, age-dependent effects of diesel exhaust particle (DEP) exposure on brain health, underscoring the urgency of reducing air pollution. The findings support stricter environmental regulations to limit DEP emissions and promote cleaner transportation alternatives. Protecting vulnerable populations, particularly the elderly, from prolonged exposure may help mitigate the long-term neurological impacts of air pollutants and reduce the public health burden.

pharmacology and toxicology↗