Ostrakhovitch Elena A, Song Eun-Suk, Stegemann Johannah E, McLeod Michael, Yamasaki Tritia R
Department of Neurology, University of Kentucky, 740 South Limestone St., Ste. J401, Lexington, KY, 40536-0284, USA.
Veterans Affairs, Lexington, KY, 40536, USA.
Sci Rep. 2025 May 4;15(1):15597. doi: 10.1038/s41598-025-99794-z.
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.
帕金森病（PD）是一种进行性神经退行性运动障碍，其特征是黑质纹状体变性以及α-突触核蛋白（α-Syn）聚集，不溶性聚集体在路易小体中积累。α-Syn的家族性突变与PD的发生有关。不溶性聚集体的积累导致神经毒性。鉴定抑制α-Syn种子活性的化合物非常重要。在这里，我们研究了硫化氢供体硫氢化钠（NaHS）抑制α-Syn聚集的潜力。我们研究了NaHS对原纤维生长动力学以及野生型（wt）和PD家族性α-Syn突变体通过自种子接种和交叉种子接种形成的α-Syn原纤维结构变化的影响。NaHS减缓了自种子接种和交叉种子接种的A53T α-Syn原纤维的形成，但没有减缓野生型原纤维的形成。我们观察到体外形成的原纤维长度减少。我们研究了其对细胞内原纤维形成的影响。在α-Syn过表达细胞模型中，NaHS显著减少了形成的寡聚体的数量和细丝长度。此外，NaHS挽救了接种野生型和突变型预形成原纤维的A53T α-Syn过表达细胞的活力。这些结果支持硫化氢对α-突触核蛋白聚集和细胞活力具有构象特异性影响，这值得进一步探索其治疗潜力。
