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Huntington's Disease Patient-Derived Astrocytes Display Electrophysiological Impairments and Reduced Neuronal Support
Veronica J Garcia1, David J Rushton1,2, Colton M Tom1
1Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Frontiers in Neuroscience
|July 19, 2019
Summary
Huntington's disease (HD) affects astrocytes, not just neurons. Patient-derived cells reveal mutant Huntingtin (mtHTT) impairs astrocyte function, impacting neuronal support and offering new therapeutic targets.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Huntington's disease (HD) is characterized by mutant Huntingtin (mtHTT) protein toxicity, primarily affecting striatal and cortical neurons.
- Glial cells, including astrocytes, also exhibit alterations in HD, but their specific role remains incompletely understood in patient-derived models.
- Previous HD models have not fully explored the impact of mtHTT on human astrocytes derived from induced pluripotent stem cells (iPSCs).
Purpose of the Study:
- To generate and characterize physiologically mature astrocytes from HD patient iPSCs.
- To investigate the functional consequences of mtHTT expression in human astrocytes.
- To assess the impact of HD astrocytes on neuronal health and function in vitro.
Main Methods:
- Generation of mature astrocytes from HD patient-derived iPSCs.
- Electrophysiological recordings to measure ion channel function (K+ currents) and cell capacitance.
- Calcium imaging to analyze spontaneous calcium wave propagation.
- Co-culture experiments with iPSC-derived neurons to assess neuronal support and protection against glutamate toxicity.
Main Results:
- HD patient-derived astrocytes exhibited hallmark HD phenotypes, including impaired inward rectifying K+ currents, prolonged spontaneous Ca2+ waves, and reduced cell membrane capacitance.
- Astrocytes from HD patients provided diminished support for the maturation of co-cultured iPSC-derived neurons.
- HD astrocytes failed to protect neurons from chronic glutamate-induced excitotoxicity.
Conclusions:
- This iPSC-based model demonstrates that mutant Huntingtin significantly impacts human astrocyte function.
- The findings broaden the understanding of HD pathogenesis beyond neuronal populations to include glial cells.
- Dysfunctional HD astrocytes represent a potential therapeutic target for Huntington's disease treatment.