Neuroendocrine and neurotrophic signaling in Huntington’s disease: Implications for pathogenic mechanisms and treatment strategies

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways.

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington’s Disease

“…While lighting conditions are a critical environmental input to this timing system, a body of recent work has lead us to appreciate that the feed/fast cycle is also a powerful regulators of the circadian system (Hamaguchi et al, 2015). While progressive, age-related SCN dysfunction has been reported in HD mouse models (Bartlett et al, 2016), a time-restricted feeding (TRF) regimen promises therapeutic potential and can benefit even SCN-lesioned mice (Hara et al, 2001; Mulder et al, 2014). For example, mice under TRF consume equivalent calories from a high-fat diet as those with ad libitum (ad lib) access yet are protected against obesity, hyperinsulinemia, and inflammation and have improved motor coordination (Hatori et al, 2012).…”

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

“…In prodromal HD patients, imaging studies using magnetic resonance imaging and positron emission tomography (PET) have shown that the hypothalamus appears affected before motor onset and that the pathological changes include loss of D2R . Importantly, HD patients suffer from a range of nonmotor features that represent disturbed functions typically regulated by the hypothalamus . These include psychiatric symptoms such as irritability, aggression, apathy and depression, sleep problems, changes in circadian rhythm and body weight changes.…”

“…Huntington disease (HD) is a fatal hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene that expresses the huntingtin (HTT) protein . It is clinically diagnosed when a person manifests with typical motor symptoms in combination with a positive gene test, which usually occurs in midlife , but circadian rhythm, sleep and other hypothalamic disturbances are observed as early as 15 years before clinical diagnosis . HD continues to progress leading to premature death around 20–25 years after motor onset.…”

The Role of Hypothalamic Pathology for Non-Motor Features of Huntington’s Disease

“…The hypothalamus is part of the larger limbic system that includes the hippocampus, gyrus cinguli, prefrontal cortex, insula, septal nuclei, amygdala, ventral striatum, ventral tegmental area and raphe nucleus [22,23]. In light of the presence of non-motor features in HD, this system has gained increasing interest for investigations of changes in clinical material and experimental models of HD (previously reviewed in [24][25][26][27]). These authors reviewed the state of knowledge of this area in HD in 2012 in this journal [28] and provides here an updated overview of the major findings made in the hypothalamus and the limbic system in HD.…”