Multi-omics and iPSCs: Strategies for Uncovering Neurodegenerative Disease Mechanisms

Friday, February 2, 2018 -
2:00pm to 3:00pm
The FUNG Auditorium
Leslie Thompson

Professor, Psychiatry & Human Behavior
School of Medicine

Neurobiology and Behavior
School of Biological Sciences

University of California, Irvine



Multi-omics and iPSCs: Strategies for Uncovering Neurodegenerative Disease Mechanisms


There is a critical need to define the state and predict the behavior of human brain cells in neurodegenerative disease. Our knowledge of these diseases and the foundation for intervening rationally in disease would be dramatically advanced by generating quantitative molecular phenotypes—cell signatures—of human neurons, astrocytes, brain microvascular endothelial cells (BMECs) and other brain cell types from healthy people and from patients with disease. Patient-derived induced pluripotent stem cells (iPSCs) provide an important resource to identify cell signatures underlying neurodegenerative disease. For Huntington’s disease (HD), a polyglutamine repeat expansion within the corresponding Huntingtin (HTT) protein primarily results in neurodegeneration of medium spiny neurons within the striatum and atrophy of the cortex. We have used unbiased ‘omics’ analysis of differentiated HD and control iPSCs to identify altered signatures in neural cell cultures. RNA-Seq analysis and epigenomic analysis identified a coordinated underlying program defined by key differentially expressed genes in glutamate/GABA signaling, axonal guidance and calcium influx that were markedly decreased in HD neural cultures, with over one-third in pathways regulating neuronal development and maturation. Treatment with Isoxazole-9, which targets these pathways, led to rescue of expanded polyglutamine repeat-associated phenotypes in cells and mice. We also undertook a transcriptome and functional analysis of (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls, demonstrating that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties as well as in signaling pathways governing these processes downstream of mutant Huntingtin. These findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery. Finally, to evaluate cell signatures for amyotrophic lateral sclerosis (ALS), the NeuroLINCS consortium is using a series of ALS and control iPSC-derived motor neurons lines to utilize transcriptomics, epigenomics, whole genome sequencing, proteomics, high content imaging, high throughput longitudinal single cell analysis and other cell-based assays using standardized and parallel differentiated iPSC motor neuron cultures. This has laid the groundwork to apply these methods to Answer ALS, to provide a comprehensive assessment of the molecular foundation of 1000 patient-derived differentiated iPSCs and ultimately integrate with clinical and biological data. Specific “omics” profiles are associated with C9orf72 and sporadic ALS subjects and integrated signatures have been generated using bioinformatics, statistics, computational biology and novel software tools to establish patterns that may lead to a better understanding of the underlying mechanisms of ALS. 


Leslie M. Thompson, PhD, is a Professor at the University of California, Irvine (UCI) in the Departments of Psychiatry and Human Behavior and Neurobiology and Behavior and a member of UCI MIND, the Sue and Bill Gross Stem Cell Center and the Center for the Neurobiology of Learning and Memory.  Dr. Thompson has studied Huntington’s disease, a devastating neurodegenerative disease, for most of her scientific career and was a member of the international consortium that identified the causative gene for HD in 1993.  The Thompson laboratory now focuses on understanding mechanisms that underlie HD and Amyotrophic Lateral Sclerosis and how this understanding can assist in developing treatments for the disease, including using induced pluripotent stem cells to model disease symptoms in a dish and CIRM-funded preclinical studies to use stem cell-based transplantation approaches for HD.  The iPSC research ranges from approaches to reduce accumulation of the mutant protein to genomic and bioinformatics analysis of patient-derived neural cells.

Dr. Thompson received her bachelors of arts degree from UC San Diego and her PhD from UCI.  She continued at UCI for her postdoctoral work in the laboratory of John Wasmuth, where she began her collaborative studies on HD.  She joined the faculty as an Assistant Professor at UCI in 2000.  Dr. Thompson is an AAAS Fellow, a member of the Hereditary Disease Foundation HD Cure Committee, Huntington Study Group Scientific Affairs Committee, and is founding Co-Editor in Chief of the Journal of Huntington’s Disease.  She is a principal investigator on the Answer ALS program, multiple grants from the National Institutes of Health, including a recent multi-institution LINCS Center grant from NIH to define cell signatures for neurodegenerative disease, and on stem cell grants funded by the California Institute for Regenerative Medicine.