Ranxhi Bedri, Bangash Zoya R, Chbihi Zachary M, Qadri Zaina, Islam Nazin N, Todi Sokol V, LeWitt Peter A, Tsou Wei-Ling
Wayne State University.
Henry Ford Health Systems.
Res Sq. 2025 May 15:rs.3.rs-6648986. doi: 10.21203/rs.3.rs-6648986/v1.
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 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.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是α-突触核蛋白的积累和聚集，这是一个决定性的病理标志。α-突触核蛋白的错误折叠和聚集破坏细胞内稳态，阻碍线粒体功能，并激活神经炎症反应，最终导致神经元死亡。最近的生物标志物研究报告称，三种L-鸟氨酸衍生的多胺的血清浓度显著增加，这与PD的进展及其临床亚型相关。然而，多胺途径在PD病理中的精确作用仍知之甚少。在本研究中，我们在帕金森病（PD）模型中探索了修饰多胺相互转化酶（PAIE）对α-突触核蛋白病表型的影响。我们评估了关键的退行性特征，包括寿命、运动功能、组织完整性和α-突触核蛋白的积累。我们发现PAIE在调节PD模型中的α-突触核蛋白毒性方面起着关键作用。敲低鸟氨酸脱羧酶1（ODC1）、亚精胺合酶（SRM）和精胺氧化酶（SMOX）可减轻α-突触核蛋白毒性，而抑制亚精胺/精胺N1-乙酰转移酶1（SAT1）和精胺合酶（SMS）则会加剧这种毒性。此外，SAT1或SMOX的过表达显著降低α-突触核蛋白毒性，强调了它们在PD中的潜在作用。这些结果突出了多胺途径在PD中的重要性，其中PAIE在管理α-突触核蛋白毒性方面至关重要，为针对PD的基本病理提供了新的视角。
