Hypothalamic and Neuroendocrine Changes in Huntingtons Disease

Abstract

Huntington's disease (HD) is neither a fatal hereditary neurodegenerative disorder without satisfactory treatments nor a cure. It is caused by a CAG repeat expansion in the huntingtin gene. The clinical symptoms involve motor-, cognitive- and psychiatric disturbances. Recent studies have shown that non-motor symptoms and signs, such as mood changes, sleep disturbances and metabolic alterations often occur before the onset of overt motor impairments. The hypothalamus is one of the main regulators of emotion, sleep and metabolism, and it is therefore possible that dysfunction of the hypothalamus and neuroendocrine circuits may, at least partly, be responsible for these non-motor symptoms in HD. Several hypothalamic and neuroendocrine changes have now been identified in clinical HD as well as in rodent models of the disease. These changes could be important both in the pathogenesis of HD, constitute biomarkers to track disease progression as well as to provide novel therapeutic targets for this devastating disease. The current state of knowledge in the area of hypothalamic and neuroendocrine changes in both patients and rodent models of HD is summarized in this review, and their potential as targets for novel treatment paradigms are discussed.

The Neuropathology of Huntington’s Disease

“…Sleep disturbances, alterations in circadian rhythm, and weight loss have been found to be altered in HD patients Petersen et al 2005;Petersen and Bjorkqvist 2006;Aziz et al 2008;Hult et al 2010). Atrophy of the lateral tuberal nucleus (LTN) in the basolateral region of the hypothalamus in HD cases was described by Vogt and Vogt (1951).…”

Microcirculation response to local cooling in patients with Huntington’s disease

“…The neural basis for the progression of the autonomic nervous system dysfuction is largely unknown [6]. The evidence of cerebral cortical and hypothalamic pathology [7][8][9][10][11] in the early stages of HD might suggest distorted activity in cortical and subcortical structures that are involved in the higher order central autonomic network (CAN) [12][13][14]. Recent research has suggested that the cortical parts of CAN are involved very early in PHD subjects [15].…”

Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

“…Although htt disruption can affect central neurons, htt is ubiquitously expressed and is involved in multiple functions, e.g. protein scaffolding, neurotrophin transport, and cell metabolism (12). Multiple HD mouse models display dysglycemia involving alterations in pancreatic ␤-cell mass and reduced insulin secretion, presumably caused by mutant htt (mhtt) accumulation in the islets of Langerhans (9,13).…”

“…These effects could be due to pathology of gonadal and hypothalamic gonadotropin-releasing hormone-containing neurons (16). * This work was supported, in whole or in part, by National Institutes of Health A crucial link between peripheral endocrine system activity and central nervous system activity is the hypothalamus, as this organ facilitates hunger, thirst, reproductive function, and circadian rhythms (12). The potential hypothalamic alterations that occur in N171-82Q mice are currently poorly characterized, yet a deeper understanding of the changes that occur may assist the development of therapeutics that target hypothalamic dysfunction in HD.…”