Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although it is characterized by progressive motor impairments, cognitive changes and psychiatric disturbances are major components of the disease. In addition, recent studies have shown that other non-motor symptoms such as alterations in sleep pattern, disruption of the circadian rhythm and increased energy metabolism are common and occur early. Emerging evidence suggests that the latter symptoms are likely results of disturbed functions of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Whereas clinical data are essential to define key pathological features of HD, animal models that can recapitulate the neurobiological and behavioral features of the disorder are critical tools to elucidate the underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine alterations as well as in highlighting novel potential disease pathways. This review summarizes the current state of knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical relevance and points to future implications for this emerging field.

Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease

“…A growing body of research has established a strong association between HD and hypothalamic dysfunction such as appetite changes [16], [54], circadian rhythm disturbance [55], and gut hormone alterations [15]. These hypothalamic defects can further lead to the unintended loss of bodyweight and dysfunctional energy metabolism such as diabetes and generalized insulin resistance.…”

Androgen Therapy in Neurodegenerative Diseases

“…Furthermore, it was found that the dysfunction and death of neocortical and basal ganglia neurons responsible for severe motor symptoms, psychosis, and dementia [ 249 ] worsened with disease progression and were manifested by progressive cognitive impairment [ 250 ]. Various clinical studies have shown that in patients with HD [ 251-254 ], symptoms were associated with a progressive alteration of the hypothalamic-pituitary-gonadal axis and changes in neuroendocrine systems [ 255 ]. Hypothalamic neurons are reduced in number accompanied by a reduction in gonadotropin-releasing hormone production [ 256 ].…”

Genetic Mouse Models of Huntington's Disease: Focus on Electrophysiological Mechanisms

“…Alterations in the hypothalamus and the endocrine system (e.g. loss of orexin-containing cells and increased cortisol levels), also play an important role in the manifestation of HD symptoms (Petersen et al, 2005; Bjorkqvist et al, 2006; Aziz et al, 2009; Petersen et al, 2009). Dysfunction in these systems lead to sleep and metabolic disturbances.…”