Modeling Huntington's disease with induced pluripotent stem cells

Abstract

Huntington’s disease (HD) causes severe motor dysfunction, behavioral abnormalities, cognitive impairment and death. Investigations into its molecular pathology have primarily relied on murine tissues; however, the recent discovery of induced pluripotent stem cells (iPSCs) has opened new possibilities to model neurodegenerative disease using cells derived directly from patients, and therefore may provide a human-cell-based platform for unique insights into the pathogenesis of HD. Here, we will examine the practical implementation of iPSCs to study HD, such as approaches to differentiate embryonic stem cells (ESCs) or iPSCs into medium spiny neurons, the cell type most susceptible in HD. We will explore the HD-related phenotypes identified in iPSCs and ESCs and review how brain development and neurogenesis may actually be altered early, before the onset of HD symptoms, which could inform the search for drugs that delay disease onset. Finally, we will speculate on the exciting possibility that ESCs or iPSCs might be used as therapeutics to restore or replace dying neurons in HD brains.

Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation

“…Compelling evidence now indicates that iPSC-based models can be used to model selected aspects of neurological and neurodegenerative disorders. [5][6][7] Besides their potential to provide important molecular insights into pathogenic mechanisms, iPSC-based cellular platforms can also be used for drug discovery in specific differentiated cell types. 8 Such platforms require replicable, efficient, and cost effective protocols to generate uniform cultures of neurons in sufficient numbers to enable screening of potentially thousands of different compounds.…”

Integrative Research of Induction of Pluripotent Stem Cells

“…It includes showing how a gene duplication in glaucoma causes the death of nerve cell clusters, and recapitulating genetic and cellular alterations associated with Huntington disease [7]. …”

Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

“…Furthermore, patient-derived iPSCs harbor all disease-associated genetic components that render GABAergic neurons susceptible to the disease. Therefore, they represent the most genetically precise model and might be helpful to further investigate genetic factors related to HD pathogenesis [53, 54]. Moreover, gene-silencing technologies based on patient-specific iPSCs may offer a way to correct this monogenic disorder, paving the road for personalized medicine [44, 55, 56].…”