Linking Biomarkers and Pathways: Investigating Polyamines' Influence on a-Synuclein in Parkinson's Disease
Recommended Citation
LeWitt PA, Todi SV, Qadri Z, Bangash Z, Chbihi Z, Ranxhi B, Tsou W. Linking Biomarkers and Pathways: Investigating Polyamines' Influence on a-Synuclein in Parkinson's Disease. Mov Disord 2023; 38:S11-S12.
Document Type
Conference Proceeding
Publication Date
11-22-2023
Publication Title
Mov Disord
Abstract
Background: This study was based on our findings that, withdisease progression, serum concentrations of four L-ornithine-derived PAs were greatly increased in PD patients. To understandmechanisms underlying these biomarker findings, we modeledinteractions of altered PA metabolism with the characteristicproteinopathy of PD, α-synuclein (α-Syn) aggregation. Ourhypothesis is that augmenting PA concentration influences α-Synmetabolism. Objective: We investigated whether ubiquitous cationiccompounds termed polyamines (PAs) and their metabolites interactwith synucleinopathy in Parkinson's disease (PD). Methods: Drosophila overexpressing α-Syn served as a model totest α-Syn pathology in PD. RNA interference (RNAi) fly lineswere crossed to the α-Syn or control lines. We targeted PAinterconverting enzymes across the entire body or specifically inneurons, to assess the impact of enzyme alterations on α-Synaggregation. Fly survival rate and locomotor rate were measuredand statistically evaluated. α-Syn aggregation was quantified usingThioflavin T assay. For immunohistochemistry staining, fly brainswere dissected and probed with an anti-α-Syn antibody. Theprotein concentration of α-Syn was measured by western blotting.To investigate the effect of altering PA concentrations, the 5human PAs (L-ornithine, putrescine, spermidine, spermine, andcadaverine) were fed to both wild type and α-Syn-augmented flies.Subsequent analyses encompassed survival rates, locomotor rates,and mitochondrial citrate synthase activity. Results: Upon suppressing spermidine synthase (SRM) andspermine oxidase (SMOX), we noted enhancements in α-Syn-augmented fly lifespan and motility, whereas inhibitingspermidine/spermine N1-acetyltransferase 1 (SAT1) led toopposite results. Moreover, feeding PAs resulted in a reduction offly survival rates in α-Syn-augmented fly, but not locomotor rate. Conclusion: Our findings translate the earlier PD biomarkerfindings into biochemical insights that may be relevant tounderstanding PD progression. These findings may help to guidethe development of clinical trials using therapeutic interventions totarget specific PA pathways.
Volume
38
First Page
S11
Last Page
S12
