Research Article: Dibucaine induces autophagic flux and reduces Ser129-phosphorylated ? -synuclein in induced pluripotent stem cell–derived neurons with SNCA duplication
Abstract:
The accumulation of ?-synuclein (?-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 ?-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 ?-synuclein (pS129 ?-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 ?-syn remain unresolved, our findings show that dibucaine induces autophagic flux and reduces pS129 ?-syn levels in disease-relevant human neurons.
Introduction:
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder, pathologically characterized by the accumulation of ?-synuclein (?-syn) aggregates—known as Lewy bodies—in dopaminergic neurons of the substantia nigra ( 1 , 2 ). Pathological ?-syn propagates in a prion-like manner by seeding endogenous ?-syn, driving disease onset and progression ( 3 , 4 ). Current dopaminergic treatments provide only symptomatic relief and often cause severe side effects, highlighting an urgent unmet medical…
Read more