A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells

作者：Burkhardt Matthew F; Martinez Fernando J; Wright Sarah; Ramos Carla; Volfson Dmitri; Mason Michael; Garnes Jeff; Vu Dang; Lievers Jeffery; Shoukat Mumtaz Uzma; Martinez Rita; Gai Hui; Blake Robert; Vai**erg Eugeni; Grskovic Marica; Johnson Charles; Irion Stefan; Bright Jessica; Cooper Bonnie; Leane Nguyen; Griswold Prenner Irene^*; Javaherian Ashkan

来源：Molecular and Cellular Neuroscience, 2013, 56: 355-364.

DOI：10.1016/j.mcn.2013.07.007

• ALS
• iPS
• TDP-43
• Digoxin
• Drug screening

Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients' fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modeling for drug screening.

• 出版日期2013-9