Chronobiology of Parkinson's disease: Past, present and future

Abstract

Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non-motor symptoms. Sleep complaints are among the most common non-motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24-h cycles that control essential physiological functions, or with side effects from levodopa medication and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such, we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology-based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed important new light on the aetiology and symptomatology of the disease and may allow for improvements in the quality of life for the millions of people with Parkinson's disease.

Keywords: Parkinson's disease; chronotherapy; circadian clocks; circadian rhythm; neurodegenerative diseases; sleep-wake disorders.

FIGURE 1

Two process model of sleep in mammals. Sleep is the result of harmony between two processes: The circadian process that relies on the circadian rhythm of light–dark cycles and the homeostatic process that depends on sleep pressure and tiredness. Sleep initiation happens when the distance between sleep pressure and circadian wakefulness is at the maximum level. Following sleep, sleep pressure decreases, and this distance reduces gradually; consequently, wakefulness occurs at the beginning of the next circadian cycle.

FIGURE 2

The clock genes network in SCN. CLOCK and BMAL1 dimers activate the E‐box element to initiate the transcription of other clock genes such as PERs, CRYs, RORs and REV‐ERBs. Binding REV‐ERBα to the RORE element of BMAL1 inhibits transcription of this gene. The expression of RORs, PERs and CRYs reaches peak level at 18:00. During the evening, PER:CRY:CK1δ/ε complexes translocate to the nucleus, and CLOCK–BMAL1 dissociates from the E‐box of target genes through CLOCK phosphorylation; consequently, the expression of genes in downstream will be suppressed. At midnight, RORα binds to the RORE of the BMAL1 and CLOCK promoters and induces their transcription. Translation of CLOCK and BMAL1 transcripts during the early morning leads to the initiation of a new cycle. Positive action is indicated by solid lines with lines ending in arrowheads, and negative action is indicated with lines ending in perpendicular lines. BMAL1, brain and muscle Arnt‐like protein 1; CLOCK, circadian locomotor output cycles protein kaput; CRY, cryptochrome; PER, period; REV‐ERBα, nuclear receptor subfamily 1 group D member; ROR, retinoic acid‐related orphan receptor; RORE, retinoic acid‐related orphan receptor response elements

FIGURE 3

A bidirectional relationship between circadian/sleep disturbances and PD diagnosis/progression. Neuroinflammation and neurodegeneration in dopaminergic neurons, originating from various genetic and environmental factors, lead to PD incidence. It seems that circadian and sleep alteration is not only an early symptom of PD but also an etiologic factor for PD occurrence. Furthermore, there is an association between sleep and circadian rhythm function with exacerbation of PD symptoms. There is also some evidence that long‐term L‐Dopa treatment may accelerate sleep and circadian rhythm manifestations in PD patients. PD, Parkinson's disease