Hypothalamic Alterations in Huntington's Disease Patients: Comparison with Genetic Rodent Models

Abstract

Unintended weight loss, sleep and circadian disturbances and autonomic dysfunction are prevalent features of Huntington's disease (HD), an autosomal dominantly inherited neurodegenerative disorder caused by an expanded CAG repeat sequence in the HTT gene. These features form a substantial contribution to disease burden in HD patients and appear to be accompanied by a number of neuroendocrine and metabolic changes, pointing towards hypothalamic pathology as a likely underlying mechanism. Neuronal inclusion bodies of mutant huntingtin, which are hallmarks of the disease, occur throughout the hypothalamus, and indicate local mutant huntingtin expression that could interfere with hypothalamic neuropeptide production. Also, several genetic rodent models of HD show features that could be related to hypothalamic pathology, such as weight loss and circadian rhythm disturbances. In these rodents, several hypothalamic neuropeptide populations are affected. In the present review, we summarise the changes in genetic rodent models of HD for individual hypothalamic nuclei, compare these observations to the hypothalamic changes that occur in HD patients, and make an inventory of the work that still needs to be done. Surprisingly, there is only limited overlap in the hypothalamic changes reported in HD patients and genetic rodent models. At present, the only similarity between the hypothalamic alterations in HD patients and genetic rodent models is a decrease in the number of orexin-expressing neurones in the lateral hypothalamus. Possible reasons for these discrepancies, as well as potential consequences for the development of novel therapeutic strategies, are discussed.

Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain

“…Despite progress in pathoanatomical research, further re‐investigation, however, is required, in order to (i) analyze the additional involvement of further subcortical regions (eg, amygdala, hypothalamus, subthalamic nucleus, claustrum), anatomically linked with the established targets of the disease process , and (ii) elucidate the morphological basis of some of the more poorly understood disease symptoms of HD patients (eg, severe unintended weight loss during the advanced disease stages of HD, and dysfunction of vertical saccades, vergence and steady fixation) .…”

The Neuropathology of Huntington’s Disease: Classical Findings, Recent Developments and Correlation to Functional Neuroanatomy

“…Thus, the traditional reductionistic view of HD as a primary and exclusive disease of the striatum has been challenged and is outdated in the meantime: the new fi ndings of neurodegeneration at multiple cortical and subcortical brain sites ultimately form the empirical base of the currently favored concept of the polyglutamine disease HD as a polytopic or multisystem degenerative disease of the human brain Lange and Aulich 1986 ;Rüb et al 2013a ;Vonsattel 2008 ). 1.4 ) (Lange et al 1976 ;Lange and Aulich 1986 ;Van Wamelen et al 2014 ;Vonsattel 2008 ;Vonsattel and DiFiglia 1998 ;Vonsattel et al 1985 ). 1 ) ( Fig.…”

Body weight is a robust predictor of clinical progression in Huntington disease

“…As the mechanisms governing the rate of motor and cognitive decline in HD are likely to be central, it is tempting to speculate that the association between BMI and disease progression in HD might be due to an effect of disturbances of energy regulating mechanisms on central nervous system function. 4 Dysregulation of energy homeostasis in HD could be mediated through pathology of central energy regulating structures, especially the hypothalamus which is known to be affected in HD, 17,18 or might arise from cellular alterations engendered by mutant huntingtin expression in peripheral tissues. 19 Our study has certain limitations.…”