Circadian clock dysfunction in Parkinson's disease: mechanisms, consequences, and therapeutic strategy

Parkinson's Disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. This leads to hallmark motor features that include bradykinesia, resting tremor, rigidity, and postural instability, alongside with a range of non-motor symptoms including sleep disturbances, mood disorders, and cognitive decline. As global life expectancy rises, the prevalence of PD is expected to continue to increase, highlighting the urgent need for effective therapeutic strategies. Despite tremendous advances in our understanding of disease-associated mechanisms, we still do not fully understand the aetiology of PD. Emerging evidence points to the circadian clock-a system that regulates physiological processes such as sleep-wake cycles and hormone release-as a critical factor in PD pathophysiology. Disruptions in circadian rhythms (CR) are common in PD patients and may exacerbate both motor and non-motor symptoms, potentially influencing the progression of neurodegeneration. This review examines the global impact of PD within the context of an aging population, delves into the molecular underpinnings of the disease, and explores the role of CR in PD. We summarize and discuss key reports on molecular links between PD and CR using unbiased systematic search strategies to cover a broad literature. Finally, we discuss the potential of chronotherapy, the alignment of treatment with the body's natural rhythms, as a personalized approach in PD management, aiming to improve treatment efficacy and patient quality of life. Understanding the interplay between circadian biology and PD could pave the way for innovative, personalized therapeutic strategies.