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The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

Emily Machiela, Ritika Jeloka, Nicholas S. Caron, Shagun Mehta, Mandi E. Schmidt, Colton M. Tom, Nalini Polturi, Yuanyun Xie, Virginia B Mattis, View ORCID ProfileMichael R. Hayden, Amber L. Southwell
doi: https://doi.org/10.1101/800268
Emily Machiela
Burnett School of Biomedical Sciences, University of Central Florida, Orlando FL
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Ritika Jeloka
Burnett School of Biomedical Sciences, University of Central Florida, Orlando FL
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Nicholas S. Caron
Centre For Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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Shagun Mehta
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Mandi E. Schmidt
Centre For Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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Colton M. Tom
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Nalini Polturi
Burnett School of Biomedical Sciences, University of Central Florida, Orlando FL
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Yuanyun Xie
Burnett School of Biomedical Sciences, University of Central Florida, Orlando FL
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Virginia B Mattis
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Michael R. Hayden
Centre For Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • ORCID record for Michael R. Hayden
Amber L. Southwell
Burnett School of Biomedical Sciences, University of Central Florida, Orlando FLCentre For Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
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  • For correspondence: amber.southwell@ucf.edu
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Abstract

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.

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Posted October 13, 2019.
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The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons
Emily Machiela, Ritika Jeloka, Nicholas S. Caron, Shagun Mehta, Mandi E. Schmidt, Colton M. Tom, Nalini Polturi, Yuanyun Xie, Virginia B Mattis, Michael R. Hayden, Amber L. Southwell
bioRxiv 800268; doi: https://doi.org/10.1101/800268
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The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons
Emily Machiela, Ritika Jeloka, Nicholas S. Caron, Shagun Mehta, Mandi E. Schmidt, Colton M. Tom, Nalini Polturi, Yuanyun Xie, Virginia B Mattis, Michael R. Hayden, Amber L. Southwell
bioRxiv 800268; doi: https://doi.org/10.1101/800268

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