Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinson's Disease

Parkinson’s Disease (PD) is a prevalent neurodegenerative disorder characterized by the accumulation and aggregation of α-synuclein as a defining pathological hallmark. Misfolding and aggregation of α-synuclein disrupt cellular homeostasis, hinder mitochondrial function, and activate neuroinflammatory responses, ultimately resulting in neuronal death. Recent biomarker studies have reported a significant increase in the serum concentrations of three L-ornithine-derived polyamines, correlating with PD progression and its clinical subtypes. However, the precise role of polyamine pathways in PD pathology remains poorly understood. In this study, we explored the impact of modifying polyamine-interconversion enzymes (PAIE) on the α-synucleinopathy phenotype in a Drosophila melanogaster model of Parkinson’s Disease (PD). We assessed key degenerative features, including lifespan, locomotor function, tissue integrity, and α-synuclein accumulation. We found that PAIEs play a critical role in modulating α-synuclein toxicity in the PD model. Knockdown of ornithine decarboxylase 1 (ODC1), spermidine synthase (SRM), and spermine oxidase (SMOX) mitigates α-synuclein toxicity, whereas suppression of spermidine/spermine N1-acetyltransferase 1 (SAT1) and spermine synthase (SMS) exacerbates it. Furthermore, the overexpression of SAT1 or SMOX significantly lowers α-synuclein toxicity, emphasizing their potential involvement in PD. These results highlight the importance of polyamine pathways in PD, where PAIEs are essential in managing α-synuclein toxicity, providing a new perspective on targeting PD’s fundamental pathology.