Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs

被引:54
作者
Hawrot, James [1 ,2 ]
Imhof, Sophie [1 ,2 ,3 ,6 ]
Wainger, Brian J. [1 ,2 ,4 ,5 ]
机构
[1] Massachusetts Gen Hosp, Dept Neurol & Anesthesia, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Dept Crit Care & Pain Med, Boston, MA 02114 USA
[3] Univ Amsterdam, Amsterdam, Netherlands
[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[5] Broad Inst Harvard Univ & MIT, Cambridge, MA 02142 USA
[6] Med Univ Vienna, Vienna, Austria
关键词
ALS; iPSCs; neurodegenerative disease; therapy; genetics; disease model; AMYOTROPHIC-LATERAL-SCLEROSIS; PLURIPOTENT STEM-CELLS; NUCLEOCYTOPLASMIC TRANSPORT DEFECTS; FRONTOTEMPORAL LOBAR DEGENERATION; C9ORF72 REPEAT EXPANSIONS; MOUSE MODEL; PATHOLOGICAL FEATURES; SPINAL MOTONEURONS; GENETIC CORRECTION; TDP-43; PATHOLOGY;
D O I
10.1016/j.nbd.2019.104680
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyotrophic lateral sclerosis (ALS) is an aggressive and uniformly fatal degenerative disease of the motor nervous system. In order to understand underlying disease mechanisms, researchers leverage a host of in vivo and in vitro models, including yeast, worms, flies, zebrafish, mice, and more recently, human induced pluripotent stem cells (iPSCs) derived from ALS patients. While mouse models have been the main workhorse of preclinical ALS research, the development of iPSCs provides a new opportunity to explore molecular phenotypes of ALS within human cells. Importantly, this technology enables modeling of both familial and sporadic ALS in the relevant human genetic backgrounds, as well as a personalized or targeted approach to therapy development. Harnessing these powerful tools requires addressing numerous challenges, including different variance components associated with iPSCs and motor neurons as well as concomitant limits of reductionist approaches. In order to overcome these obstacles, optimization of protocols and assays, confirmation of phenotype robustness at scale, and validation of findings in human tissue and genetics will cement the role for iPSC models as a valuable complement to animal models in ALS and more broadly among neurodegenerative diseases.
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页数:16
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