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bioRxiv · 10.1101/2025.03.06.641237

Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinsons disease

Ranxhi, B.·Bangash, Z. R.·Chbihi, Z. M.·Qadri, Z.·Islam, N. N.·Todi, S. V.·LeWitt, P. A.·Tsou, W.-L.
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Abstract

Parkinson's Disease (PD) is a prevalent neurodegenerative disorder with the accumulation and aggregation of alpha-synuclein (&[alpha]-Syn) as a central pathological hallmark. Misfolding and aggregation of &[alpha]-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 &[alpha]-Syn. Our findings reveal a 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 &[alpha]-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 &[alpha]-Syn levels and mitigate neurodegeneration in PD.

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Ranxhi, B., Bangash, Z. R., Chbihi, Z. M., Qadri, Z., Islam, N. N., Todi, S. V., LeWitt, P. A., Tsou, W.-L.. 2025-03-11. Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinsons disease. https://doi.org/10.1101/2025.03.06.641237

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