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 with the accumulation and aggregation of alpha-synuclein (α-Syn) as a central pathological hallmark. Misfolding and aggregation of α-Syn disrupts cellular homeostasis, hinders mitochondrial function, and activates neuroinflammatory responses, ultimately resulting in neuronal death. Recent biomarker research indicated a notable increase in the serum concentrations of three L-ornithine-derived polyamines (PAs): putrescine, spermidine, and spermine, each correlating with the progression of PD and its clinical subtypes. However, the role of PA pathways in PD pathology is poorly understood; it is unclear whether elevated PA concentrations are linked to PD pathology, or whether they represent a secondary effect. In this study, we targeted PAs through RNAi knockdown of different PA-interconversion enzymes (PAIE) in a Drosophila melanogaster model of PD that overexpresses human, wild-type α-Syn. Our findings reveal significant impact on both the lifespan and motility of PD-model flies when crucial PAIE, such as ornithine decarboxylase 1 (ODC1), spermidine synthase (SRM), spermidine/spermine N1-acetyltransferase 1 (SAT1), and spermine oxidase (SMOX) are targeted. The overexpression of SAT1 and SMOX in this PD model had positive, enduring effects on fly lifespan. Additionally, we noted significant alterations in ⍺-Syn protein levels when PAIE are either knocked down or overexpressed. These findings underscore the role of PA pathways in PD and their potential targeting to modulate ⍺-Syn levels and mitigate neurodegeneration in PD.