Abstract
Huntington’s disease (HD) is a neurodegenerative disorder characterized by the progressive decline of motor, cognitive, and psychiatric functions. HD results from an autosomal dominant mutation that causes a trinucleotide CAG repeat expansion and the production of mutant Huntingtin protein (mHTT). This results in the initial selective and progressive loss of medium spiny neurons (MSNs) in the striatum before progressing to involve the whole brain. There are currently no effective treatments to prevent or delay the progression of HD as knowledge into the mechanisms driving the selective degeneration of MSNs has been hindered by a lack of access to live neurons from individuals with HD. The invention of cell reprogramming provides a revolutionary technique for the study, and potential treatment, of neurological conditions. Cell reprogramming technologies allow for the generation of live disease-affected neurons from patients with neurological conditions, becoming a primary technique for modelling these conditions in vitro. The ability to generate HD-affected neurons has widespread applications for investigating the pathogenesis of HD, the identification of new therapeutic targets, and for high-throughput drug screening. Cell reprogramming also offers a potential autologous source of cells for HD cell replacement therapy. This review provides a comprehensive analysis of the use of cell reprogramming to model HD and a discussion on recent advancements in cell reprogramming technologies that will benefit the HD field.
Highlights
Huntington’s disease (HD) is a devastating neurodegenerative disorder for which there is currently no effective treatment
Alterations in calcium signalling genes were only observed in HD induced pluripotent stem cells (iPSCs)-derived neural progenitor/precursor cells (NPC) from an HD line with 60 CAG repeats [45]. These results indicate that disease-associated phenotypes in HD iPSC-derived NPCs may depend on the CAG repeat length and the corresponding disease severity
Similar to HD iPSCs, most studies conducted in HD iPSC-derived NPCs did not report a degenerative phenotype, and increased caspase activity under standard culture conditions was only observed in HD iPSC-derived NPCs from a juvenile 180 CAG repeat line [45]
Summary
Huntington’s disease (HD) is a devastating neurodegenerative disorder for which there is currently no effective treatment. The revolutionary ability of cell reprogramming to generate human neurons in vitro for disease modelling was catalysed by the discovery that hESCs could be isolated from embryos affected by genetic disorders [2,4]. Cell death was only observed in HD or genetically modified HD hESC-derived neurons upon kinase inhibition [19] or growth factor withdrawal [17]. Disease-associated phenotypes have been reported in hESCs and hESC-derived neural progenitor/precursor cells (NPC) in HD and genetically modified HD cell lines. Seriola et al observed the downregulation of DNA mismatch repair genes upon neural induction of both normal and HD hESCs [21] Together, this indicates that the differentiation process itself may interfere with the phenotype of hESC-derived cells, with the CAG repeat expansion exacerbating these effects
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