Dibucaine induces autophagic flux and reduces Ser129-phosphorylated α-synuclein in induced pluripotent stem cell–derived neurons with SNCA duplication

The accumulation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites is a neuropathological hallmark of Parkinson’s disease (PD) and is closely associated with disease progression. Targeting the autophagy pathway to enhance the clearance of α-syn aggregates therefore represents a promising therapeutic strategy. In the present study, we conducted high-throughput screening using rat embryonic primary neurons, followed by validation of the identified compounds in human induced pluripotent stem cell (iPSC)-derived neurons. We identified dibucaine, a local anesthetic, as a compound that induced autophagic flux in neuronal models. In human iPSC-derived dopaminergic neurons from a patient with PD carrying an SNCA duplication, dibucaine reduced cellular levels of Ser129-phosphorylated α-synuclein (pS129 α-syn). In SH-SY5Y cells, dibucaine increased 5’-AMP-activated protein kinase (AMPK) Thr172 phosphorylation. LY364947 partially attenuated dibucaine-induced LC3-II accumulation in the iPSC-derived neurons through an unidentified mechanism. Although the requirement for AMPK and the mechanism underlying the reduction in pS129 α-syn remain unresolved, our findings show that dibucaine induces autophagic flux and reduces pS129 α-syn levels in disease-relevant human neurons.