'The clocks that time us'--circadian rhythms in neurodegenerative disorders

Abstract

Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep-wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep-wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep-wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases.

Figure 1

A simplified scheme of the circadian system. The timing of human biological rhythms is synchronized to the rotation of the Earth, and is influenced by numerous external and internal time cues. These stimuli are known as ’zeitgebers’ (German for ‘time giver’). Light is the most important and potent zeitgeber. In addition to light, activity, feeding schedules, and the hormone melatonin also influence circadian timing. This synchronization can become disrupted, which eventually leads to misalignment or internal desynchronization. This loss of coordination of circadian rhythms can have negative consequences for sleep–wake cycles and numerous other biological functions.

Figure 2

Molecular organization of the circadian system. The proteins encoded by the core set of clock genes—PER, CLOCK, ARNTL (also known as BMAL1) and CRY—interact to create a self-sustaining negative transcription–translation feedback loop. The intracellular level of CLOCK remains steady throughout the 24 h period. The high level of ARNTL at the beginning of the day promotes the formation of ARNTL–CLOCK heterodimers, which in turn activate transcription of PER and CRY. As PER accumulates in the cytoplasm, it becomes phosphorylated and degraded by ubiquitylation. CRY accumulates in the cytoplasm late in the subjective day, and translocates to the nucleus to inhibit ARNTL–CLOCK-mediated transcription. At night, the PER–CRY complex is degraded, and the cycle starts again. This feedback loop ensures a high level of ARNTL and low levels of PER and CRY at the beginning of a new circadian day.