Abstract

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, the underlying pathogenic mechanisms of PD remain incompletely defined, and effective treatments are lacking. N-acetyltransferase 10 (NAT10) catalyzes N4-acetylcytidine (ac4C) modification of mRNA, a process crucial for mRNA stability and translational efficiency. However, whether NAT10-mediated ac4C modification contributes to PD and the molecular mechanisms underlying its involvement remain unclear. This study aimed to investigate the role of NAT10 and its ac4C-mediated transcriptomic regulation in PD and to elucidate the underlying molecular mechanisms. In vivo and in vitro PD models were generated, and the expression levels of NAT10 and global ac4C modification were assessed. Experimental results revealed that NAT10 expression and global RNA ac4C levels were significantly increased in PD models and were positively associated with dopaminergic neuronal apoptosis. Knockdown of NAT10 reduced dopaminergic neuronal apoptosis, while overexpression exacerbated this apoptosis. Mechanistically, NAT10 may enhance ac4C modification of pyruvate dehydrogenase kinase 1 (PDK1) mRNA, thereby increasing its stability and translational efficiency. Upregulated PDK1 promoted phosphorylation of the pyruvate dehydrogenase (PDH) E1α subunit, leading to reduced PDH complex activity, decreased adenosine triphosphate (ATP) production, and increased lactate accumulation, possibly contributing to dopaminergic neuronal apoptosis. Importantly, treatment with the NAT10-targeting compound Remodelin alleviated dopaminergic neuron loss and improved motor deficits in PD models. Collectively, these findings suggest that NAT10/ac4C-associated dysfunction of the PDK1/PDH axis contributes to altered energy metabolism and dopaminergic neuronal apoptosis in PD models, supporting NAT10 as a potential intervention target for PD.