Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity

IF 2.4 4区医学 Q3 NEUROSCIENCES

Neuroscience Research Pub Date : 2025-03-01 DOI:10.1016/j.neures.2024.11.007

Maierdanjiang Nuermaimaiti , Kei-ichi Ishikawa , Genko Oyama , Risa Nonaka , Takahiro Shiga , Takayuki Jo , Taiji Tsunemi , Ryota Nakamura , Rejko Krüger , Wado Akamatsu , Nobutaka Hattori

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Abstract

Lewy body diseases, including Parkinson's disease (PD), are characterized by the spread of alpha-synuclein (αSyn) between neurons across synapses, a process crucial for understanding their pathophysiology and developing effective treatments. In this study, we aimed to investigate the role of neuronal activity in releasing αSyn from human induced pluripotent stem cell-derived dopaminergic neurons. We examined human induced pluripotent stem cell-derived dopaminergic neurons, both healthy and those with the αSyn gene mutation associated with PD. We employed pharmacological agents and optogenetic techniques and demonstrated that increased neuronal activity, induced by bicuculline or optogenetic stimulation, significantly enhances αSyn release. However, suppression of neuronal activity with cyanquixaline reduces αSyn secretion. These findings underscore the pivotal role of neuronal activity in αSyn transmission between neurons, showing its potential impact on the spread of Lewy pathology in patients with neurodegenerative diseases like PD. Therefore, this study advances our understanding of PD and opens new avenues for therapeutic strategies to mitigate Lewy body disease progression.

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人诱导多能干细胞衍生的多巴胺能神经元通过神经元活动释放α -突触核蛋白。

路易体疾病，包括帕金森氏病（PD），其特征是α -突触核蛋白（αSyn）在突触神经元之间的传播，这一过程对于理解其病理生理和开发有效的治疗方法至关重要。在这项研究中，我们旨在研究神经元活动在人诱导多能干细胞衍生的多巴胺能神经元释放αSyn中的作用。我们检测了人类诱导的多能干细胞衍生的多巴胺能神经元，包括健康的和αSyn基因突变与PD相关的神经元。我们利用药物和光遗传技术证明，在双球茎碱或光遗传刺激下，神经元活性的增加显著促进α - syn的释放。然而，用氰喹喹啉抑制神经元活性会减少αSyn的分泌。这些发现强调了神经元活动在神经元间αSyn传递中的关键作用，显示了其对PD等神经退行性疾病患者Lewy病理扩散的潜在影响。因此，本研究促进了我们对PD的理解，并为减轻路易体疾病进展的治疗策略开辟了新的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuroscience Research 医学-神经科学

CiteScore

5.60

自引率

3.40%

发文量

136

审稿时长

28 days

期刊介绍： The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.