Induced Pluripotent Stem Cells from Patients with Huntington's Disease Show CAG-Repeat-Expansion-Associated Phenotypes

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, the HD consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics.

Use of differentiated pluripotent stem cells in replacement therapy for treating disease

“…Nonetheless, some transplanted PD patients did experience durable benefit, providing at least a proof-of-principal in favor of dopaminergic neuronal transplantation. The generation of midbrain dopaminergic neurons (64, 65) and medium spiny neurons (66, 67) from human PSCs (64–67) thus permit a leap forward in the availability of well-defined engraftable neurons of relative phenotypic homogeneity. This advance should enable a new generation of therapeutic trials less compromised by donor variability and compositional heterogeneity.…”

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…iPS cell technologies have been used to examine the mechanisms of multiple disorders including amyotrophic lateral sclerosis (ALS) (Egawa et al. 2012), Huntington's disease (HD) (HD iPSC Consortium 2012), and Parkinson's disease (PD) (Devine et al. 2011).…”

Cell-Based Screening: Extracting Meaning from Complex Data

“…For example, efficient protocols have been developed to make neural crest by dual-SMAD inhibition/WNT activation (Chambers et al, 2013). Protocols have been reported for making many brain cell types from stem cells, including dopaminergic neurons (Studer, 2012; Sun et al, 2013; Sundberg et al, 2013), motor neurons (Bilican et al, 2012; Boulting et al, 2011; Di Giorgio et al, 2007), forebrain-like neurons (HD iPSC Consortium et al, 2012), striatal neurons (Aubry et al, 2008), cortical interneurons (Maroof et al, 2013), retinal cells (Jin and Takahashi, 2012); oligodendrocytes (Czepiel et al, 2011; Ogawa et al, 2011; Wang et al, 2013; Yang et al, 2013) and astrocytes (Emdad et al, 2012; Serio et al, 2013). Neurons and neural progenitors can be produced directly from other types of somatic cells without having to first make those cells pluripotent (Ambasudhan et al, 2011; Kim et al, 2011; Vierbuchen et al, 2010).…”

“…For the first time, a skin or blood cell from a patient with a neurological or psychiatric disease can be reprogrammed to become a cell type of the nervous system, thereby creating a genetically faithful human model of disease (Churko et al, 2013; Hayes and Zavazava, 2013; Wray et al, 2012). Already, several models have been developed that exhibit disease-relevant phenotypes (Table 1) for Huntington's disease (HD) (HD iPSC Consortium et al, 2012; Zhang et al, 2010), amyotrophic lateral sclerosis (ALS) (Barmada et al; Bilican et al, 2012; Burkhardt et al, 2013; Donnelly et al, 2013; Egawa et al, 2012; Sareen et al, 2013; Serio et al, 2013), spinal muscular atrophy (Ebert et al, 2009), Parkinson's disease (Cooper et al, 2012; Skibinski et al, 2014), schizophrenia (Brennand et al, 2011), and Alzheimer's disease (AD)(Israel et al, 2012). In principle, genetic and small-molecule screens can be conducted in what might be the most physiologically relevant cell-based model of neurological disease ever developed.…”