Neurodegenerative Disease Huntington’s Disease

The Role of Hypothalamic and Neuroendocrine Changes in the Pathogenesis of Huntington’s Disease – Current Understanding and Implications for Future Treatments

Åsa Petersén Associate Professor, Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University

Abstract

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that leads to premature death. There is no satisfactory treatment or cure. The disease is caused by an expanded CAG repeat in the huntingtin gene. The clinical features are characterised by progressive motor symptoms, including chorea, which currently defines the clinical diagnosis of the disease. The motor aspect of HD is thought to be due to dysfunction and cell loss in the striatum of the basal ganglia. Cognitive impairment and psychiatric disturbances occur early and are major components of the disease. Recent studies have shown that other non-motor symptoms and signs, such as disruption of the circadian rhythm, sleep disturbances, autonomic dysfunction and metabolic changes, are also common and occur early. Several of these non-motor features are likely results of dysfunction of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Increasing numbers of reports are now redefining HD as a disease with pathology spreading beyond the basal ganglia. This article provides an overview of current knowledge based on recent clinical studies demonstrating that hypothalamic and neuroendocrine changes are important features of HD.

Keywords Huntingtin, Huntington’s disease, hypothalamus, orexin, oxytocin

Disclosure: The author has no conflicts of interest to declare. Acknowledgement: Åsa Petersén is supported by the Swedish Research Council and the Bagadilico network, an excellence research centre on basal ganglia disorders. Received: 11 October 2010 Accepted: 19 November 2010 Citation: European Neurological Review, 2010;5(2):49–53 Correspondence: Åsa Petersén, Translational Neuroendocrine Research Unit, BMC D11, 221 84 Lund, Sweden. E: Asa.Petersen@med.lu.se

Huntington’s disease (HD) is a monogenetic disorder with a spectrum of clinical features. Besides the characteristic involuntary motor disturbances, such as chorea, individuals affected by the disease suffer from psychiatric symptoms and cognitive decline.1–3

Despite

this, focus on the movement disorder in clinical practice and the research of HD has been strong.

In recent years, studies of non-motor symptoms and signs in HD have revealed that sleep disturbances, disruption of the circadian rhythm, autonomic dysfunction and metabolic alterations are also common and occur early on in the disease process. Therefore the conventional notion that HD is solely a movement disorder caused by selective basal ganglia pathology had to be challenged.

The fact that the hypothalamus and its neuroendocrine circuitries are important regulators of emotion, sleep and bodyweight has stimulated research investigating to what extent this system is affected in HD. Although further studies are needed, the current literature now provides strong support for hypothalamic pathology and neuroendocrine alterations to be included as part of the clinical phenotype of HD.

This article reviews the current state of knowledge in terms of the clinical relevance of hypothalamic and neuroendocrine changes in HD.

© TOUCH BRIEFINGS 2010

The Genetics of Huntington’s Disease This hereditary and monogenetic neurodegenerative disease has a prevalence of around 1:10,000.1

It is caused by an expanded CAG

repeat in the huntingtin gene, which codes for an expanded polyglutamine in the huntingtin protein.4

This protein is expressed in

all tissues in the body. Although huntingtin protein’s normal function is not fully known, it is thought to involve vesicle transport, transcriptional regulation and synaptic function.5,6

CAG repeats of 40

or more cause the disease with full penetrance, with onset of motor symptoms in midlife. Huntingtin genes with between 37 and 39 CAG repeats have reduced penetrance. Intermediate repeats between 29 and 35 do not cause the disease but may expand to a pathogenic range in future generations. Juvenile onset (<20 years of age) occurs with more than 60 to 70 CAG repeats. Hence, longer CAG repeats are associated with a younger age of onset. The CAG repeat length accounts for around 60% of the variance in age of onset; genetic and/or environmental factors are thought to cause the rest.7 Interestingly, the genetic modifiers that have so far been reported to influence the age of onset in HD include factors involved in the regulation of metabolism, such as huntingtin-associated protein 1 (HAP1) and PPARγ coactivator-1α (PGC-1α).8,9

Predictive and diagnostic genetic testing for HD is now available. Despite this, only around 15% of all individuals who develop the

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