Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, the Netherlands.
Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, the Netherlands.
Cell Calcium. 2021 Mar;94:102362. doi: 10.1016/j.ceca.2021.102362. Epub 2021 Jan 30.
Progressive neuronal loss is a hallmark of many neurodegenerative diseases, including Alzheimer's and Parkinson's disease. These pathologies exhibit clear signs of inflammation, mitochondrial dysfunction, calcium deregulation, and accumulation of aggregated or misfolded proteins. Over the last decades, a tremendous research effort has contributed to define some of the pathological mechanisms underlying neurodegenerative processes in these complex brain neurodegenerative disorders. To better understand molecular mechanisms responsible for neurodegenerative processes and find potential interventions and pharmacological treatments, it is important to have robust in vitro and pre-clinical animal models that can recapitulate both the early biological events undermining the maintenance of the nervous system and early pathological events. In this regard, it would be informative to determine how different inherited pathogenic mutations can compromise mitochondrial function, calcium signaling, and neuronal survival. Since post-mortem analyses cannot provide relevant information about the disease progression, it is crucial to develop model systems that enable the investigation of early molecular changes, which may be relevant as targets for novel therapeutic options. Thus, the use of human induced pluripotent stem cells (iPSCs) represents an exceptional complementary tool for the investigation of degenerative processes. In this review, we will focus on two neurodegenerative diseases, Alzheimer's and Parkinson's disease. We will provide examples of iPSC-derived neuronal models and how they have been used to study calcium and mitochondrial alterations during neurodegeneration.
进行性神经元丢失是许多神经退行性疾病的标志，包括阿尔茨海默病和帕金森病。这些病理学表现出明显的炎症、线粒体功能障碍、钙失调和聚集或错误折叠蛋白质的积累迹象。在过去的几十年中，大量的研究工作有助于确定这些复杂的脑神经退行性疾病中神经退行性过程的一些病理机制。为了更好地了解负责神经退行性过程的分子机制，并找到潜在的干预和药物治疗方法，拥有能够重现破坏神经系统维持的早期生物学事件和早期病理事件的强大体外和临床前动物模型非常重要。在这方面，确定不同的遗传致病性突变如何损害线粒体功能、钙信号和神经元存活将是有启发性的。由于死后分析不能提供有关疾病进展的相关信息，因此开发能够研究早期分子变化的模型系统至关重要，这些变化可能是新的治疗选择的相关靶点。因此，人类诱导多能干细胞（iPSC）的使用代表了研究退行性过程的一个极好的补充工具。在这篇综述中，我们将重点介绍两种神经退行性疾病，即阿尔茨海默病和帕金森病。我们将提供 iPSC 衍生神经元模型的示例，并展示它们如何用于研究神经退行性过程中的钙和线粒体改变。
