Kaus Anjoscha, Sareen Dhruv
Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center Los Angeles, CA, USA ; Department of Biomedical Sciences, Cedars-Sinai Medical Center Los Angeles, CA, USA.
Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center Los Angeles, CA, USA ; Department of Biomedical Sciences, Cedars-Sinai Medical Center Los Angeles, CA, USA ; iPSC Core, The David and Janet Polak Stem Cell Laboratory, Cedars-Sinai Medical Center Los Angeles, CA, USA.
Front Cell Neurosci. 2015 Nov 19;9:448. doi: 10.3389/fncel.2015.00448. eCollection 2015.
Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this "chicken or egg" causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased 'OMICS and high-throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS.
肌萎缩侧索硬化症（ALS）是一种主要为散发性的进行性神经退行性疾病，影响上下运动神经元（MNs），其具体病因尚未完全明确。在部分家族性和散发性患者中已发现超氧化物歧化酶-1（SOD1）、TAR DNA结合蛋白43（TARDBP/TDP-43）和C9orf72的突变。关键的相关分子和神经病理学特征包括泛素化的TDP-43包涵体、应激颗粒、来自突变C9orf72转录本的聚集二肽蛋白、线粒体超微结构改变、钙稳态失调、氧化应激和内质网（ER）应激以及未折叠蛋白反应（UPR）。这些损伤在ALS动物模型中已有记录；然而，这些机制是导致ALS患者MN易损性的起始因素还是后期的继发事件仍存在争议。人类诱导多能干细胞（iPSCs）是一种有价值的工具，可以解决这种“先有鸡还是先有蛋”的因果困境。本文描述了用于从大量ALS患者中探测病理生理受影响细胞并发现早期MN易感性的表型疾病特征的相关系统。在一组ALS患者iPSC来源的相关神经细胞中进行无偏倚的“组学”和高通量筛选，并挽救线粒体和内质网应激损伤，可以确定针对增加ALS患者MN寿命的靶向治疗方法。
