Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease
Open accessAbstract
Sleep disturbances in neurological disorders have a devastating impact on patient and carer alike. However, their pathological origin is unknown. Here we show that patients with Huntington's disease (HD) have disrupted night-day activity patterns. This disruption was mirrored in a transgenic model of HD (R6/2 mice) in which daytime activity increased and nocturnal activity fell, eventually leading to the complete disintegration of circadian behavior. The behavioral disturbance was accompanied by marked disruption of expression of the circadian clock genes mPer2 and mBmal1 in the suprachiasmatic nuclei (SCN), the principal circadian pacemaker in the brain. The circadian peak of expression of mPer2 was prematurely truncated, and the mRNA levels of mBmal1 were attenuated and failed to exhibit a significant circadian oscillation. Circadian cycles of gene expression in the motor cortex and striatum, markers of behavioral activation in wild-type mice, were also suppressed in the R6/2 mice, providing a neural correlate of the disturbed activity cycles. Increased daytime activity was also associated with reduced SCN expression of prokineticin 2, a transcriptional target of mBmal1 encoding a neuropeptide that normally suppresses daytime activity in nocturnal mammals. Together, these molecular abnormalities could explain the pathophysiological changes in circadian behavior. We propose that circadian sleep disturbances are an important pathological feature of HD, that they arise from pathology within the SCN molecular oscillation, and that their treatment will bring appreciable benefits to HD patients.
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Circadian and sleep misalignment likely influence the neurodegenerative process itself.
“Of note, circadian and sleep misalignment likely influence the neurodegenerative process itself (Ju et al., 2014, Mamelak, 1997, Morton et al., 2005).”
From Circadian dysregulation in Parkinson's disease (2017) · cites this paper as Morton et al., 2005
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Self-citation
- Authors
- Morton, A. J., Wood, N. I., Hastings, M. H., Hurelbrink, C., Barker, R. A., & Maywood, E. S.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- Addenbrooke's Hospital (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-01-05
- Volume
- 25
- Issue
- 1
- Pages
- 157-163
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725210
- OpenAlex
- W2126357344
- Cited by
- 403
- References
- 43
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 21 · 2023: 11 · 2022: 16 · 2021: 14 · 2020: 12 · 2019: 30 · 2018: 18 · 2017: 29 · 2016: 26 · 2015: 24 · 2014: 21 · 2013: 22 · 2012: 24
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alexander and Margaret Stewart Trust
- Hereditary Disease Foundation
- Sir Halley Stewart Trust
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- Huntington's disease, circadian rhythm, sleep-wake cycle, clock genes, mPer2, suprachiasmatic nucleus, R6/2 mice, prokineticin 2, diurnal activity, nocturnal activity, striatum, motor cortex, circadian gene expression, sleep disorders
- MeSH terms
- Adult, Aged, Animals, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Huntington Disease, Male, Mice, Transgenic, Middle Aged, Motor Activity, Suprachiasmatic Nucleus, Sleep Disorders, Circadian Rhythm, Dyssomnias, Chronobiology Disorders, Mice
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