Dopaminergic neurons are vulnerable to dysregulation of YEATS2-dependent calcium homeostasis

Abstract

YEATS2 is a ubiquitously expressed chromatin-associated factor that we recently identified as a novel regulator of dopaminergic (DAergic) synaptic integrity, though its mechanism of action remained unclear. Using Drosophila, we show that neuronal depletion of YEATS2 reshapes the brain transcriptome, marked by downregulation of metabolic genes and upregulation of G protein-coupled receptors (GPCRs). These changes coincide with elevated intracellular calcium, neurobehavioral deficits, and selective DA neuron loss. Importantly, genetic or pharmacological inhibition of the store-operated calcium entry channel Orai restored calcium homeostasis and rescued DA neuron survival. Our findings define a YEATS2-dependent epigenetic-calcium axis that governs DA neuron vulnerability.