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

Using Drosophila, we show that neuronal depletion of YEATS2 alters brain transcriptomes, downregulating metabolic genes and upregulating G protein–coupled receptors (GPCRs). This correlates with elevated intracellular calcium levels, leading to neurobehavioral deficits and selective DA neuron loss.

Crucially, genetic or pharmacological inhibition of the store-operated calcium entry channel Orai restores calcium balance and rescues DA neuron survival. These findings reveal a YEATS2-dependent epigenetic–calcium axis critical for dopaminergic neuron vulnerability.