Fig.1 Progression of Huntington's disease over a patient's lifespan. (Ross, 2011)
Huntington's disease (HD), an incurable hereditary progressive neurodegenerative disorder accompanied by symptoms, such as dementia, chorea, and depression, is caused by the loss of the GABAergic medium spiny neurons (MSNs) in the striatum. Degeneration of GABAergic MSNs causes an empty space in the brain, which is greatly increased in the HD patient brain. For individuals affected with HD, there is an expansion of the CAG repeat region within the huntingtin (HTT)-encoding genes, resulting in aggregates of polyglutamine. The clinical course of HD is progressive for many years, ultimately leading to severe brain atrophy and death. The disease is inherited in an autosomal dominant manner, and it occurs at a rate of 4-10 individuals per 100,000 population, mostly in 30-40-year-olds. However, therapeutic agents for the treatment of HD have not yet been developed.
Importance of In Vitro Models in HD
To study HD pathology, researchers have relied on animal models. Animal models have revealed many fundamental findings, however, animal models suffer from various drawbacks: (1) The use of animals for research has raised ethical concerns from animal rights groups; (2) There is a wide gap between animal and human physiology, so one must always extrapolate animal data to predict the human scenario. Animal models, for the aforementioned reasons, are increasingly falling out of favor. Therefore, researchers have developed more suitable in vitro systems to elucidate HD pathophysiology.
Application of In Vitro Models in AD Research
Until now, many stem cell-based 2D in vitro HD models have been developed, but a limited number of relevant physiological models exist. For example, Zhang et al. used suspensions of self-aggregating HD-iPS cells to generate NSCs. Within this 3D system, the HD-NSCs differentiated into striatal neurons containing the same CAG expansion found in the HD patient from whom the iPS cell line was established. Such differentiated cells could serve as a human HD cell model to analyze its pathophysiology or for drug screening.
Model Cell Type
-elevated caspase activity upon growth factor deprivation
-neuroprotective effect of CGS21680 and APEC ► therapeutic potential
-higher levels of FOXO1 and FOXO4 ► elevated proteasome activity
iPSC- GABA+ neurons
-under treatment with memantine ► reversal of HD pathologic events
HD monkey iPSC-astrocytes
-detection of numerous HD related pathologiesm ► HTT aggregates, inefficient glutamate clearance, suppression of mitochondrial function abnormal electrophysiology
Corrected HD iPSC-NPCs
-after transplantation into mice model ► survival and differentiation of cells into the GABAergic neurons
-after bilateral transplantation into mice striatum ► improved locomotor function
mice HD iPSCs/human HD iPSCs
-dysregulation of ERK signaling, P-catenin phosphorylation, SOD1 accumulation, and p53 expression
-high number of significantly dysregulated mRNAs
-increased calcium SOC activity; treatment by quinazoline derivative - EVP4593 led to reduced activity of SOC currents and normalization of calcium transport
HD monkey iPSC-NPCs
-under treatment with memantine, Rilizole and Methylene blue ► the most potent anti-apoptotic drug was Rilizole; the most effective in reduction of mTT aggregates was Methylene blue
Corrected HD monkey iPSC-GABA+ neurons
-after transplantation into mice striatum ► longer lifespan of HD mice model; improved behavioral and locomotor function
Services at Creative Biolabs
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Ross, C. A. and Tabrizi, S. J. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10(1): 83-98.