Tsunemi Taiji, Ishiguro Yuta, Yoroisaka Asako, Feng Dou, Shimada Tomoyo, Niiyama Shunichi, Sasazawa Yukiko, Ishikawa Keiichi, Akamatsu Wado, Hattori Nobutaka
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
J Neurosci. 2025 Mar 12;45(11):e2350232024. doi: 10.1523/JNEUROSCI.2350-23.2024.
Parkinson's disease is characterized by the presence of alpha-synuclein (α-syn) primarily containing Lewy bodies in neurons. Despite decades of extensive research on α-syn accumulation, its molecular mechanisms have remained largely unexplored. Recent studies by us and others have suggested that extracellular vesicles (EVs), especially exosomes, can mediate the release of α-syn from cells and inhibiting this pathway could result in increased intracellular α-syn levels. In this study, we have discovered that elevated levels of α-syn themselves lead to reduced α-syn -containing EVs in α-syn-inducible H4 cells and induced pluripotent stem cell-derived dopaminergic (DA) neurons from both sexes. Our investigations have revealed that the impairment in EV secretion is not due to their generation but rather a consequence of changes in a soluble -ethylmaleimide-sensitive factor attachment protein receptor protein, YKT6. Specifically, as α-syn levels increase, membrane-associated YKT6 is reduced. Pharmacological inhibition of farnesylation using FTI has led to decreased EV secretion and subsequent elevated levels of α-syn. In summary, our findings suggest that increased levels of α-syn impair YKT6-mediated EV secretion, establishing a detrimental cycle of intracellular α-syn accumulation in human DA neurons.
帕金森病的特征是在神经元中存在主要包含路易小体的α-突触核蛋白（α-syn）。尽管对α-syn积累进行了数十年的广泛研究，但其分子机制在很大程度上仍未得到探索。我们和其他人最近的研究表明，细胞外囊泡（EVs），尤其是外泌体，可以介导α-syn从细胞中释放，抑制这一途径可能导致细胞内α-syn水平升高。在这项研究中，我们发现α-syn水平升高本身会导致α-syn诱导的H4细胞以及来自两性的诱导多能干细胞衍生的多巴胺能（DA）神经元中含α-syn的EVs减少。我们的研究表明，EV分泌受损不是由于它们的产生，而是可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体蛋白YKT6变化的结果。具体而言，随着α-syn水平的增加，膜相关的YKT6减少。使用FTI对法尼基化进行药理抑制导致EV分泌减少以及随后α-syn水平升高。总之，我们的研究结果表明，α-syn水平升高会损害YKT6介导的EV分泌，在人类DA神经元中建立细胞内α-syn积累的有害循环。
