Beccano-Kelly Dayne A, Cherubini Marta, Mousba Yassine, Cramb Kaitlyn M L, Giussani Stefania, Caiazza Maria Claudia, Rai Pavandeep, Vingill Siv, Bengoa-Vergniory Nora, Ng Bryan, Corda Gabriele, Banerjee Abhirup, Vowles Jane, Cowley Sally, Wade-Martins Richard
Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK.
iScience. 2023 Jun 7;26(7):107044. doi: 10.1016/j.isci.2023.107044. eCollection 2023 Jul 21.
Parkinson's disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the - mutation, a strong genetic risk factor for PD. iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD.
帕金森病（PD）的特征是运动和认知功能逐渐恶化。虽然多巴胺神经元死亡是PD的标志性病理特征，但这是一个在神经元功能障碍之后的晚期疾病过程。在此，我们描述了携带-突变的患者来源的诱导多能干细胞（iPSC）-多巴胺神经元中的早期生理扰动，该突变是PD的一个强大遗传风险因素。iPSC-多巴胺神经元显示出早期且持续的钙调节异常，特别是在线粒体处，随后线粒体膜电位和氧消耗率降低，表明线粒体功能衰竭。随着神经元成熟度增加，我们观察到PD iPSC-多巴胺神经元的突触功能下降，这与随着时间推移支持电生理活动增加所需的ATP和钙一致。我们的研究表明，钙稳态失调和线粒体功能衰竭损害了成熟神经元的较高电生理活性，可能是PD中多巴胺神经元易损性的基础。
