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Published on: December 10, 2021
Hypothalamic alterations in Huntington's disease patients: comparison with genetic rodent models
D J van Wamelen1, N A Aziz, R A C Roos
1Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam ZO, The Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Insights
Huntington's disease (HD) causes weight loss and sleep issues, possibly due to hypothalamic dysfunction. Rodent models show limited overlap with human HD hypothalamic changes, except for reduced orexin neurons.
Area of Science:
- Neuroscience
- Genetics
- Metabolic disorders
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by unintended weight loss, sleep disturbances, and autonomic dysfunction.
- These symptoms suggest hypothalamic pathology, as mutant huntingtin inclusions are found in the hypothalamus, potentially disrupting neuropeptide production.
Purpose of the Study:
- To review and compare hypothalamic changes in genetic rodent models of HD with those observed in human HD patients.
- To identify discrepancies and similarities in hypothalamic alterations between models and patients to guide future research and therapeutic strategies.
Main Methods:
- Systematic review of studies on genetic rodent models of HD, focusing on hypothalamic nuclei and neuropeptide populations.
- Comparison of findings from rodent models with reported hypothalamic changes in human HD patients.
Main Results:
- Significant discrepancies exist between hypothalamic alterations reported in HD patients and genetic rodent models.
- The only consistent similarity identified is a decrease in orexin-expressing neurons in the lateral hypothalamus in both HD patients and rodent models.
Conclusions:
- Current genetic rodent models of HD do not fully recapitulate the hypothalamic pathology seen in human patients.
- Further research is needed to understand these discrepancies and develop more accurate models for therapeutic development in Huntington's disease.
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.
