Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease
Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease
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DOI：
10.1111/ejn.14345
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发表时间：
2019-02
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通讯作者：
Beatrice Weykopf;S. Haupt;Johannes Jungverdorben;L. Flitsch;Matthias Hebisch;Guang-Hui Liu;Keiichiro Suzuki;J. Belmonte;M. Peitz;S. Blaess;A. Till;O. Brüstle
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作者：
Beatrice Weykopf;S. Haupt;Johannes Jungverdorben;L. Flitsch;Matthias Hebisch;Guang-Hui Liu;Keiichiro Suzuki;J. Belmonte;M. Peitz;S. Blaess;A. Till;O. Brüstle
细胞重编程的最新进展使得能够评估患者源性体细胞中的疾病相关细胞性状，从而为疾病建模和药物开发提供了一个通用平台。鉴于对重要人脑细胞的获取有限，这项技术特别适用于神经退行性疾病，如帕金森病（PD），作为破译潜在病理机制的工具。重要的是，基因组编辑技术的最新进展提供了分析仅在单一遗传变化中不同的同基因诱导多能干细胞（iPSC）对的能力，从而允许对单基因风险因素导致的分子和细胞表型进行全面评估。在这篇综述中，我们总结了基于iPSC的PD建模的现状，重点是富含亮氨酸的重复序列激酶2（LRRK2），这是与家族性和特发性形式相关的PD最突出的单基因风险因素之一。LRRK2蛋白是一种主要的胞质多结构域蛋白，有助于调节多种途径，包括自噬、线粒体功能、囊泡转运、核结构和细胞形态。我们总结了基于iPSC的研究，这些研究有助于提高我们对LRRK2及其变体在PD病因学背景下的功能的理解。这些数据，沿着在我们自己的研究中获得的结果，强调了LRRK 2在几个水平上调节细胞稳态的多方面作用，包括蛋白质稳态、线粒体动力学和细胞骨架的调节。最后，我们阐述了重编程技术用于疾病建模和药物开发的优势和局限性，并对这一令人兴奋的技术所带来的未来挑战和期望进行了展望。
Recent advances in cell reprogramming have enabled assessment of disease‐related cellular traits in patient‐derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome‐editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC‐based modeling of PD with a focus on leucine‐rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi‐domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC‐based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.