Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson's Disease.

IF 6.7 1区 医学 Q1 NEUROSCIENCES
Fikret Emre Kapucu, Iisa Tujula, Oskari Kulta, Lassi Sukki, Tomi Ryynänen, Hjalte Gram, Valtteri Vuolanto, Andrey Vinogradov, Joose Kreutzer, Poul Henning Jensen, Pasi Kallio, Susanna Narkilahti
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Abstract

Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson's disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived neuronal cultures and in engineered networks. Here, we report an engineered circular tripartite human neuronal network model in a microfluidic chip integrated with microelectrode arrays (MEAs) as a platform to study functional markers during α-s aggregation and propagation. We observed progressive aggregation of α-s in conventional neuronal cultures and in the exposed (proximal) compartments of circular tripartite networks following exposure to preformed α-s fibrils (PFF). Furthermore, aggregated forms propagated to distal compartments of the circular tripartite networks through axonal transport. We observed impacts of α-s aggregation on both the structure and function of neuronal cells, such as in presynaptic proteins, mitochondrial motility, calcium oscillations and neuronal activity. The model enabled an assessment of the early, middle, and late phases of α-s aggregation and its propagation during a 13-day follow-up period. While our temporal analysis suggested a complex interplay of structural and functional changes during the in vitro propagation of α-s aggregates, further investigation is required to elucidate the underlying mechanisms. Taken together, this study demonstrates the technical potential of our introduced model for conducting in-depth analyses for revealing such mechanisms.

Abstract Image

用于对帕金森病中α-突触核蛋白聚集和传播进行时间评估的人类三方皮层网络模型。
以往的研究表明,聚集的α-突触核蛋白(α-s)蛋白是帕金森病(PD)的主要病理标志物,可在细胞间传播,从而参与疾病的进展。人们利用体内和体外模型(包括啮齿动物和人类细胞培养物)对这种朊病毒样传播进行了广泛研究。在这项研究中,我们的重点是在人类诱导多能干细胞(hiPSC)衍生的神经元培养物和工程网络中对α-s聚集和传播过程中的功能变化进行时间评估。在这里,我们报告了一个在微流控芯片中集成了微电极阵列(MEA)的工程化环形三方人类神经元网络模型,以此为平台研究α-s聚集和传播过程中的功能标记。我们观察到α-s在传统的神经元培养物中逐渐聚集,并在暴露于预成的α-s纤维(PFF)后的环形三方网络的暴露(近端)区块中逐渐聚集。此外,聚集形式通过轴突运输传播到圆形三方网络的远端区室。我们观察到α-s聚集对神经元细胞结构和功能的影响,如突触前蛋白、线粒体运动、钙振荡和神经元活动。该模型能够评估α-s聚集的早期、中期和晚期阶段及其在13天随访期内的传播情况。我们的时间分析表明,α-s 聚集体在体外传播过程中,结构和功能变化相互作用,情况复杂,但要阐明其潜在机制,还需要进一步研究。总之,本研究证明了我们引入的模型在进行深入分析以揭示此类机制方面的技术潜力。
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
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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