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Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2 ALS pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2 ALS model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2 ALS and other ER stress-related conditions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luca Lo Piccolo reports financial support was provided by Chiang Mai University. Luca Lo Piccolo reports financial support was provided by Health System Research Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Histone acylation plays a pivotal role in modulating gene expression, ensuring proper neurogenesis and responsiveness to various signals. Recently, the evolutionary conserved YAF9, ENL, AF9, TAF41, SAS5 (YEATS) domain found in four human paralogs, has emerged as a new class of histone acylation reader with a preference for the bulkier crotonyl group lysine over acetylation. Despite advancements, the role of either histone crotonylation or its readers in neurons remains unclear. In this study, we employed Drosophila melanogaster to investigate the role of ENL/AF9 (dENL/AF9) in the nervous system. Pan-neuronal dENL/AF9 knockdown not only extended the lifespan of flies but also enhanced their overall fitness during aging, including improved sleep quality and locomotion. Moreover, a decreased activity of dENL/AF9 in neurons led to an up-regulation of catalase gene expression which combined with reduced levels of malondialdehyde (MDA) and an enhanced tolerance to oxidative stress in aging flies. This study unveiled a novel function of histone crotonylation readers in aging with potential implications for understanding age-related conditions in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)