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.
Highlights
Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded polyglutamine encoding CAG tract in the huntingtin (HTT) gene (MacDonald et al, 1993)
We found that H2O2 induced Reactive oxygen species (ROS) in control neurons (Figure 1A; two way analysis of variance (ANOVA) treatment p = 0.0021, genotype 0.8977, Bonferroni post-test different from neurobasal complete (NBC) Hu18/18: 50 μM, p = 0.0773; 100 μM, p = 0.0133; 150 μM, p = 0.0227), but failed to induce ROS in HD neurons (Different from NBC Hu97/18 18 50 μM, p = 0.6155; 100 μM, p = 0.9986; 150 μM, p = 0.0390)
We found a similar effect in menadione-treated neurons, with the induction of ROS in control, but not HD, neurons (Figure 1B, treatment p = 0.0196, genotype p = 0.4051, post-test vs. phosphate-buffered saline (PBS) same genotype Hu18/18: p = 0.0050; Hu97/18: p > 0.9999)
Summary
Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded polyglutamine encoding CAG tract in the huntingtin (HTT) gene (MacDonald et al, 1993). Age-of-onset of HD is negatively correlated with CAG tract length (Andrew et al, 1993a,b; Snell et al, 1993). This only explains ∼50–70% of the variation in disease ageof-onset, with other genetic and environmental factors making up the remainder (Wexler et al, 2004). Patients with the same expanded CAG tract length can have differences in disease onset of up to 50 years. Those with identical mutations can progress at different rates. This suggests that factors aside from the CAG repeat can have a strong influence on disease pathogenesis
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