Transient reduction of neuronal electrical activity replenishes energy levels and protects PARK2 patient- derived neurons against oxidative stress

Abstract Ageing-associated metabolic decline compromises neuronal repair and accelerates neurodegeneration, yet strategies to restore neuronal energy balance remain limited. Here, we show in human neural cultures that pharmacological or optogenetic inhibition of neuron electrical activity raises their ATP levels, or replenishes them during mild mitochondrial impairment. Transiently reducing neuron electrical activity enhances lysosomal function and protects from oxidative toxicity. To test relevance to Parkinson’s disease (PD), we identify targetable ion channel subunits enriched in vulnerable substantia nigra dopaminergic neurons. Modulating these channels, including inwardly rectifying potassium channels, nicotinic acetylcholine receptors, and cyclic nucleotide-gated cation channels, increases ATP in human substantia nigra-patterned cultures. PD patient-derived and CRISPR-engineered PARK2 -mutant dopaminergic neurons exhibit heightened oxidative-stress vulnerability, which is reduced by modulating the activity of broadly expressed voltage-gated sodium channels as well as more substantia nigra-specific channels. These findings identify neuronal electrical activity modulation as a neuroprotective mechanism and support its further preclinical investigation as a complementary and tunable strategy to mitigate bioenergetic stress in neurodegenerative disorders.