AUTHOR=Machiela Emily , Jeloka Ritika , Caron Nicholas S. , Mehta Shagun , Schmidt Mandi E. , Baddeley Helen J. E. , Tom Colton M. , Polturi Nalini , Xie Yuanyun , Mattis Virginia B. , Hayden Michael R. , Southwell Amber L. TITLE=The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons JOURNAL=Frontiers in Aging Neuroscience VOLUME=12 YEAR=2020 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2020.524369 DOI=10.3389/fnagi.2020.524369 ISSN=1663-4365 ABSTRACT=

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. 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 the brains of HD 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 neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.