Pre-symptomatic proteomic and metabolomic profiling identifies compensated ER-redox-metabolic adaptation and early nuclear vulnerability in neuronal ERO1L toxicity

Aging leads to challenges in neuronal proteostasis, redox homeostasis, and metabolism, but the early molecular changes that precede functional decline are not well understood. Endoplasmic reticulum oxidoreductin 1 (ERO1) plays a crucial role in linking endoplasmic reticulum (ER) proteostasis with cellular redox balance and is known to increase in aging and neurodegenerative contexts.

Researchers investigated how the elevated ERO1L protein expression alters cellular homeostasis before the onset of dysfunction in Drosophila melanogaster. As flies age, endogenous ERO1L expression rises, and higher levels of neuronal ERO1L shorten lifespan and lead to progressive locomotor decline. However, this effect was only observed in neurons and not in other cell types like glia, muscle, or fat body.

By day 5 post-eclosion, when locomotor performance was still intact and major brain reactive-oxygen-species (ROS) accumulation was negligible, a pre-symptomatic stage was identified. Multi-omic profiling at this stage showed changes in ER proteostasis, redox defense, and mitochondrial-energy pathways, along with alterations in central-carbon, nitrogen, and purine metabolism.

Unlike these adaptable responses, chromatin- and RNA-homeostasis-associated proteins, including HP1, dFmr1, and Piwi, were reduced, accompanied by an increase in transposable-element transcripts. This pre-symptomatic state in neuronal ERO1L elevation exhibits proteostatic and metabolic adaptation concurrently with early vulnerability in nuclear and RNA-homeostasis pathways, occurring before the onset of oxidative stress and behavioral decline.

These findings present an in vivo framework to study how age-associated ERO1L elevation might progressively diminish neuronal resilience during brain aging.