Cell Reprogramming to Model Huntington’s Disease: A Comprehensive Review

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.

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

“…posttranslational modifications [258], proteostasis [259], autophagy [260,261], redox homeostasis [262], metabolism [263,264], HTT mRNA [265,266], Ca 2+ and dopamine signaling [61], inflammation [267], in vitro modelling of HD [268,269], striatal neurogenesis [270], stem cell treatment [271][272][273][274][275][276][277][278][279], electric stimulation therapy [280], network connectivity in presymptomatic HD brain [281], non-motor symptoms [282], gut microbiome [283], human immunodeficiency virus [284], diagnosis [285,286], clinical progression [287], treatment for the symptoms [288], physical therapy [289], psychological interventions [290,291], and management of agitation [292]. Collectively, the previous studies have potential to reveal spatiotemporal and cell-type specific mechanism of HD pathology.…”

Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

“…Human data from HD patients derive mainly from post-mortem samples, taken mainly for histochemistry studies, thus representing the end stage of the disease. In recent years, it has become possible to generate human-induced pluripotent stem cells (hiPSC), and this capacity of reprogramming human fibroblast into neurons in vitro has aided in the study of HD [ 239 ]. Regarding glial cells, there are a few studies that have used hiPSC to generate these cells.…”