Sleep and Circadian clock in Parkinson’s disease
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterised by the progressive deterioration of dopaminergic neurons. Nearly 2 % of the global population are affected and as a result, PD patients suffer from motor abnormalities including difficulty in movement and tremor. Additional non-motor symptoms such as neuropsychiatric, behavioural and sensory alterations have been retrospectively associated with Parkinson’s disease. More recently, circadian and sleep pattern disturbance has been reported in patients, suggesting a role of the circadian system in the exacerbation of disease symptoms. Circadian rhythms are endogenous oscillations of key biological processes such as hormone release, body temperature and brain function that help our bodies operate. Scientists with the EU-funded CircaDopamine project wished to further investigate how circadian rhythms are affected in Parkinson’s disease. They worked on the rationale that in mammals, circadian rhythms are aligned with the light/dark cycle through light input from the retina to the hypothalamus and then through the activation of specific circadian clock genes. This part of the hypothalamus then transduces information through both neuronal and humoral signals (via the circulatory system) to many central and peripheral regions. ‘Circadian rhythms control motor actions, food intake, as well as cognitive functions such as learning, memory, and decision making,’ explains Dr Karim Fifel. ‘This takes place partially through dopaminergic neurons,’ he continues. By identifying the circadian component of dopaminergic signalling, the CircaDopamine consortium wanted to shed light on the physiological processes controlled by this neuronal pathway and how they are disturbed in Parkinson’s disease. In humans, lack of sleep has been traditionally linked with various cardiovascular, mental and metabolic diseases but the mechanism remains unknown. As such, there are no effective therapeutic strategies available to alleviate sleep and circadian rhythm malfunction which may exacerbate disease condition. Linking the circadian clock with dopaminergic signalling To scientifically address how circadian rhythms operate in Parkinson’s disease, the scientists followed an experimental approach based on two transgenic mouse models, namely MitoPark and CircaDA. The MitoPark model mimicked the progressive age-dependent neurodegeneration of dopaminergic neurons seen in Parkinson’s disease patients. Significant for the project research, the CircaDA model lacked a functional circadian clock specifically in dopaminergic neurons. Researchers investigated the consequences of dopaminergic signalling loss on sleep regulation and performed in vivo electrophysiology monitoring to study the role of the circadian changes in dopaminergic neurotransmission. Through different light regimes, they also examined the effect of photoperiod on sleep and dopamine function. To further identify the members of the molecular pathways used by dopamine to regulate clock gene oscillations, researchers used selective dopamine receptor drugs and measured neuronal function. Clinical significance The results of the CircaDopamine project have provided fundamental insight into the connection between the circadian clock and dopaminergic neurotransmission. Collectively, the findings help comprehend the impact that light, including short and long photoperiods, may have on sleep and on the electrophysiology of the dopaminergic neurotransmission. From a clinical perspective this information provides the basis for understanding how the circadian network operates in Parkinson’s disease. In addition, it opens a new window for the management of sleep alterations and circadian abnormalities in a number of dopamine-related psychological and neurological disorders. In this context, light therapy may comprise a beneficial treatment that aims to alleviate sleep disturbance and its consequences in patients with neurodegeneration. Importantly, ‘the results suggest that future drug development efforts should incorporate the concept of chronomedicine,’ envisages Dr Fifel.
