PT  - JOURNAL ARTICLE
AU  - Emily Machiela
AU  - Ritika Jeloka
AU  - Nicholas S. Caron
AU  - Shagun Mehta
AU  - Mandi E. Schmidt
AU  - Colton M. Tom
AU  - Nalini Polturi
AU  - Yuanyun Xie
AU  - Virginia B Mattis
AU  - Michael R. Hayden
AU  - Amber L. Southwell
TI  - The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons
AID  - 10.1101/800268
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 800268
4099  - http://biorxiv.org/content/early/2019/10/13/800268.short
4100  - http://biorxiv.org/content/early/2019/10/13/800268.full
AB  - 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.