title: Modeling Huntington׳s disease with patient-derived neurons.
abstract: Huntington׳s Disease (HD) is a fatal neurodegenerative disorder caused by expanded polyglutamine repeats in the Huntingtin (HTT) gene. While the gene was identified over two decades ago, it remains poorly understood why mutant HTT (mtHTT) is initially toxic to striatal medium spiny neurons (MSNs). Models of HD using non-neuronal human patient cells and rodents exhibit some characteristic HD phenotypes. While these current models have contributed to the field, they are limited in disease manifestation and may vary in their response to treatments. As such, human HD patient MSNs for disease modeling could greatly expand the current understanding of HD and facilitate the search for a successful treatment. It is now possible to use pluripotent stem cells, which can generate any tissue type in the body, to study and potentially treat HD. This review covers disease modeling in vitro and, via chimeric animal generation, in vivo using human HD patient MSNs differentiated from embryonic stem cells or induced pluripotent stem cells. This includes an overview of the differentiation of pluripotent cells into MSNs, the established phenotypes found in cell-based models and transplantation studies using these cells. This review not only outlines the advancements in the rapidly progressing field of HD modeling using neurons derived from human pluripotent cells, but also it highlights several remaining controversial issues such as the 'ideal' series of pluripotent lines, the optimal cell types to use and the study of a primarily adult-onset disease in a developmental model. This article is part of a Special Issue entitled SI: Exploiting human neurons.
authors.affiliation: The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP 8102, Los Angeles, CA 90048, USA. Electronic address: Virginia.Mattis@cshs.org.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Mattis
authors.affiliation: The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AHSP 8102, Los Angeles, CA 90048, USA.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
mesh_terms: D000818:Animals; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology* / Q000628:therapy; D057026:Induced Pluripotent Stem Cells / Q000502:physiology / Q000637:transplantation; D009474:Neurons / Q000502:physiology* / Q000637:transplantation
keywords: Embryonic stem cell (ESC); Huntingtin (HTT); Huntington׳s disease (HD); Induced pluripotent stem cell (iPSC); Modeling