Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel 24118, Germany.
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Neurobiol Dis. 2019 Jul;127:147-162. doi: 10.1016/j.nbd.2019.01.018. Epub 2019 Feb 19.
Lysosomes are organelles involved in the degradation and recycling of macromolecules, and play a critical role in sensing metabolic information in the cell. A class of rare metabolic diseases called lysosomal storage disorders (LSD) are characterized by lysosomal dysfunction and the accumulation of macromolecular substrates. The central nervous system appears to be particularly vulnerable to lysosomal dysfunction, since many LSDs are characterized by severe, widespread neurodegeneration with pediatric onset. Furthermore, variants in lysosomal genes are strongly associated with some common neurodegenerative disorders such as Parkinson's disease (PD). To better understand disease pathology and develop novel treatment strategies, it is critical to study the fundamental molecular disease mechanisms in the affected cell types that harbor endogenously expressed mutations. The discovery of methods for reprogramming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), and their differentiation into distinct neuronal and glial cell types, have provided novel opportunities to study mechanisms of lysosomal dysfunction within the relevant, vulnerable cell types. These models also expand our ability to develop and test novel therapeutic targets. We discuss recently developed methods for iPSC differentiation into distinct neuronal and glial cell types, while addressing the need for meticulous experimental techniques and parameters that are essential to accurately identify inherent cellular pathologies. iPSC models for neuronopathic LSDs and their relationship to sporadic age-related neurodegeneration are also discussed. These models should facilitate the discovery and development of personalized therapies in the future.
溶酶体是参与大分子降解和回收的细胞器，在细胞中感应代谢信息方面发挥着关键作用。一类称为溶酶体贮积症（LSD）的罕见代谢疾病的特征是溶酶体功能障碍和大分子底物的积累。中枢神经系统似乎特别容易受到溶酶体功能障碍的影响，因为许多 LSD 都表现为严重、广泛的神经退行性变，发病于儿童期。此外，溶酶体基因的变异与一些常见的神经退行性疾病（如帕金森病（PD））密切相关。为了更好地了解疾病病理学并开发新的治疗策略，研究携带内源性突变的受影响细胞类型中的基本分子疾病机制至关重要。利用患者来源的体细胞重编程为诱导多能干细胞（iPSC）的方法的发现，以及它们分化为不同的神经元和神经胶质细胞类型，为研究溶酶体功能障碍的机制提供了新的机会。这些模型还扩展了我们开发和测试新治疗靶点的能力。我们讨论了最近开发的用于将 iPSC 分化为不同神经元和神经胶质细胞类型的方法，同时解决了需要精心设计实验技术和参数的问题，这些技术和参数对于准确识别固有细胞病理学至关重要。神经元溶酶体贮积症的 iPSC 模型及其与散发性年龄相关性神经退行性变的关系也进行了讨论。这些模型应有助于未来发现和开发个性化治疗方法。
