Biological Aging and the Cellular Pathogenesis of Huntington’s Disease

Abstract

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin gene ( HTT ). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life, suggesting that aging may play an active role in pathogenesis. Cellular aging is defined as the slow decline in stress resistance and accumulation of damage over time. While different cells and tissues can age at different rates, 9 hallmarks of aging have emerged to better define the cellular aging process. Strikingly, many of the hallmarks of aging are also hallmarks of HD pathology. Models of HD and HD patients possess markers of accelerated aging, and processes that decline during aging also decline at a more rapid rate in HD, further implicating the role of aging in HD pathogenesis. Furthermore, accelerating aging in HD mouse and patient-derived neurons unmasks HD-specific phenotypes, suggesting an active role for the aging process in the onset and progression of HD. Here, we review the overlap between the hallmarks of aging and HD and discuss how aging may contribute to pathogenesis in HD.

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.…”

Huntington’s Disease: Current Advances and Future Prospects

“…The shortening of the telomeres leads to several neurodegenerative diseases. HD leukocytes have the shortest telomeres, among all the neurodegenerative diseases [2]. The following table 1 represents the presence or absence of HD.…”

“…It occurs by the repetition of cytosine, adenine and guanine (CAG) trinucleotide on the chromosome 4p16.3 in the huntingtin gene [1]. This huntingtin gene gets translated into a mutant huntingtin protein (mHTT) [2]. In HD the symptoms are analogous to several other diseases.…”

The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration

“…DNA damage is now widely implicated in aging and the pathophysiology of age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) (Madabhushi et al, 2014 ; Machiela and Southwell, 2020 ). However, emerging evidence suggests that DNA damage and DNA repair are not only induced by pathological conditions (Ju et al, 2006 ; Tiwari et al, 2012 ; Suberbielle et al, 2013 ; Madabhushi et al, 2015 ).…”