Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons.
Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons.
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钙调节异常结合线粒体衰竭和电生理成熟度在帕金森病的iPSC多巴胺神经元中聚集。
DOI：
10.1016/j.isci.2023.107044
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发表时间：
2023-07-21
期刊：
影响因子：
5.8
通讯作者：
Wade-Martins, Richard
中科院分区：
文献类型：
--
作者：
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
帕金森病（PD）的特征是运动和认知功能的进行性恶化。虽然多巴胺神经元的死亡是PD的标志性病理，但这是一个晚期疾病过程，之前是神经元功能障碍。在这里，我们描述了患者来源的诱导多能干细胞(iPSC)-多巴胺神经元携带GBA-N370S突变的早期生理扰动，这是PD的一个强大的遗传危险因素。GBA-N370S ipsc -多巴胺神经元表现出早期和持续的线粒体钙异常，随后线粒体膜电位和耗氧率降低，表明线粒体功能衰竭。随着神经元成熟度的增加，我们观察到PD ipsc -多巴胺神经元突触功能下降，这与ATP和钙的需求一致，以支持随着时间的推移电生理活动的增加。我们的研究表明，钙平衡失调和线粒体衰竭损害了成熟神经元较高的电生理活动，可能是PD中多巴胺神经元易感性的基础。GBA-N370S ipsc -多巴胺神经元显示PD相关表型的时间序列，在我们的PD模型中，钙信号被PLD1和iPLA2减少扰乱，线粒体效率降低导致ATP产生减少。细胞神经科学;干细胞研究
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 GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S 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. GBA-N370S iPSC-dopamine neurons demonstrate a temporal sequence of PD related phenotypes Calcium signaling is disrupted in our PD model by reduced PLD1 and iPLA2 Reduced mitochondrial efficiency resulted in reduced ATP production Our model GBA-PD system shows for the first time a reduced synaptic function Pathophysiology; Cellular neuroscience; Stem cells research
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影响因子：
9
作者：
Gómez-Suaga P;Bravo-San Pedro JM;González-Polo RA;Fuentes JM;Niso-Santano M
通讯作者：
Niso-Santano M
影响因子：
4
作者：
Dason, Jeffrey S.;Romero-Pozuelo, Jesus;Atwood, Harold L.
通讯作者：
Atwood, Harold L.
影响因子：
6.1
作者：
Cherubini, Marta;Lopez-Molina, Laura;Gines, Silvia
通讯作者：
Gines, Silvia
DOI：
10.1523/jneurosci.2519-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Guzman JN;Sánchez-Padilla J;Chan CS;Surmeier DJ
通讯作者：
Surmeier DJ
影响因子：
5.3
作者：
Beccano-Kelly DA;Kuhlmann N;Tatarnikov I;Volta M;Munsie LN;Chou P;Cao LP;Han H;Tapia L;Farrer MJ;Milnerwood AJ
通讯作者：
Milnerwood AJ