The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons

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.

IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model

“…Therefore, metabolic manipulations have also been considered as a possible therapeutic tool for several neurodegenerative diseases, including HD ( Walker and Raymond, 2004 ; Duan et al., 2003 ; Procaccini et al., 2016 ). Interestingly, the IKK-β pathway in the hypothalamus has also been shown to be a key for the advancement of aging in mice ( Zhang et al., 2013 ) and aging is thought to be involved in HD pathogenesis ( Machiela et al., 2020 ; Machiela and Southwell, 2020 ). Given that the wild-type HTT also has a role in regulating metabolism, as it has been shown by body weight gain phenotype in YAC18 mice ( Pouladi et al., 2010 ) and by using hypothalamic expression of HTT fragments with 18Q in mice ( Soylu-Kucharz et al., 2015 ; Baldo et al., 2013 ), the IKK-β pathway has the potential to induce accelerated aging in HD by linking HTT clearance, metabolism alterations, and aging processes.…”

Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

“…In response to damage from oxidative stress, HTT localizes to the site of DNA damage and recruits DNA repair proteins [ 71 ]. Accumulation of mtHTT impairs this stress response and makes neurons more sensitive to ROS [ 72 ]. The combined presence of mtHTT and endotoxins causes microglia to release more inflammatory cytokines [ 73 ].…”

Cell Reprogramming to Model Huntington’s Disease: A Comprehensive Review

“…Similarly, while artificial aging using progerin has been considered as an alternative method of encouraging age-related pathologies in iPSC models of neurodegenerative disorders [ 22 ], the physiological relevance of this technique is questionable [ 100 ]. Machiela et al demonstrated that adeno-associated virus (AAV) transduction of progerin in iPSC-derived NPCs resulted in increased damage in differentiated HD cells but not controls, although both the differentiated control and HD cells exhibited reduced dendritic lengths and similar caspase activation when transduced with progerin as iPSC-derived NPCs [ 31 ]. As two of the three HD iPSC lines investigated by Machiela et al were from juvenile cases of HD, the specificity of artificially induced aging to model the changes that occur before adult-onset HD are called into question.…”