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Neurotherapeutics. 2019 Dec 2. doi: 10.1007/s13311-019-00810-8. [Epub ahead of print]

Modeling Polyglutamine Expansion Diseases with Induced Pluripotent Stem Cells.

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Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.
Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.


Polyglutamine expansion disorders, which include Huntington's disease, have expanded CAG repeats that result in polyglutamine expansions in affected proteins. How this specific feature leads to distinct neuropathies in 11 different diseases is a fascinating area of investigation. Most proteins affected by polyglutamine expansions are ubiquitously expressed, yet their mechanisms of selective neurotoxicity are unknown. Induced pluripotent stem cells have emerged as a valuable tool to model diseases, understand molecular mechanisms, and generate relevant human neural and glia subtypes, cocultures, and organoids. Ideally, this tool will generate specific neuronal populations that faithfully recapitulate specific polyglutamine expansion disorder phenotypes and mimic the selective vulnerability of a given disease. Here, we review how induced pluripotent technology is used to understand the effects of the disease-causing polyglutamine protein on cell function, identify new therapeutic targets, and determine how polyglutamine expansion affects human neurodevelopment and disease. We will discuss ongoing challenges and limitations in our use of induced pluripotent stem cells to model polyglutamine expansion diseases.


Huntington’s disease; Triplet repeat disorders; induced pluripotent stem cells.; neurodegeneration; polyglutamine


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