Parkinson's disease: When the gears of time stiffen — The life-and-death game of circadian rhythms, sleep disorders, and neurodegeneration

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by motor symptoms and pervasive non-motor manifestations, with over 80% of patients experiencing disrupted sleep architecture, rapid eye movement sleep behavior disorder, or circadian rhythm disorders. Notably, sleep abnormalities often precede motor symptoms and correlate with dopaminergic neuron loss, highlighting their role as potential biomarkers and accelerators of neurodegeneration. Circadian disruptions in PD manifest as altered core body temperature rhythms, delayed cortisol/melatonin secretion, and peripheral clock desynchronization, driven by α-synuclein pathology in the suprachiasmatic nucleus, mitochondrial dysfunction, and neuroinflammation. These disturbances exacerbate oxidative stress, impair protein homeostasis, and disrupt metabolic-immune crosstalk, forming a vicious cycle that accelerates neuronal degeneration. Sleep disorders in PD, including sleep behavior disorder, insomnia, and circadian misalignment, arise from neurotransmitter imbalances (dopamine, serotonin), suprachiasmatic nucleus degeneration, and gut-brain axis dysregulation. Such disruptions impair glymphatic clearance, worsen motor fluctuations, and hasten cognitive decline. Conversely, neurodegeneration in PD disrupts sleep–wake regulation, creating a bidirectional pathogenic loop. Current therapies, while alleviating motor symptoms, often aggravate circadian-sleep dysfunction. Emerging chronotherapeutic strategies, such as timed light exposure, melatonin receptor agonists, circadian-aligned drug delivery, and microbiome modulation, aim to restore rhythm synchrony, showing promise in clinical trials. Innovations like CRISPR-based clock gene editing, wearable biosensors, and AI-driven chronotherapy optimization further underscore the shift toward precision "time medicine". This review underscores the imperative to incorporate circadian and sleep health into PD diagnostics and therapeutics, heralding a new era of chronobiology-informed precision medicine.