Molecular Mechanisms Underlying Reciprocal Interactions Between Sleep Disorders and Parkinson’s Disease

Abstract

Sleep–wake disruptions are among the most prevalent and burdensome non-motor symptoms of Parkinson’s disease (PD). Clinical studies have demonstrated that these disturbances can precede the onset of typical motor symptoms by years, indicating that they may play a primary function in the pathogenesis of PD. Animal studies suggest that sleep facilitates the removal of metabolic wastes through the glymphatic system via convective flow from the periarterial space to the perivenous space, upregulates antioxidative defenses, and promotes the maintenance of neuronal protein homeostasis. Therefore, disruptions to the sleep–wake cycle have been associated with inefficient metabolic clearance and increased oxidative stress in the central nervous system (CNS). This leads to excessive accumulation of alpha-synuclein and the induction of neuronal loss, both of which have been proposed to be contributing factors to the pathogenesis and progression of PD. Additionally, recent studies have suggested that PD-related pathophysiological alterations during the prodromal phase disrupt sleep and circadian rhythms. Taken together, these findings indicate potential mechanistic interactions between sleep–wake disorders and PD progression as proposed in this review. Further research into the hypothetical mechanisms underlying these interactions would be valuable, as positive findings may provide promising insights into novel therapeutic interventions for PD.

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

“…Sleep disturbances are commonly associated with neurodegenerative diseases and are known to greatly affect the quality of life of patients [ 119 ]. For example, sleep disorders, such as nighttime insomnia, daytime hypersomnia, and rapid eye movement (REM) sleep disorders, are often seen in patients with AD [ 159 , 188 ] or PD [ 77 , 253 ]. Many effective sedative-hypnotic drug products, including benzodiazepine and Z-drugs (e.g., zolpidem, zaleplon, zopiclone) are used to induce and/or maintain sleep in people with sleep disorders.…”

Parkinson’s Disease: A Narrative Review on Potential Molecular Mechanisms of Sleep Disturbances, REM Behavior Disorder, and Melatonin

“…Neural mechanisms involved in sleep disturbances in PD [ 79 , 80 ], and even in sleep disturbance itself [ 81 , 82 ], are so complicated. Neurodegeneration in PD (and also other neurodegenerative disorders) directly affects sleep/wakefulness mechanisms and leads to sleep disturbance [ 83 ].…”

“…Of note, the dopaminergic transmission sends the circadian signal (that originated in the suprachiasmatic nucleus (SCN)) to downstream target neuronal networks, and this role may be an explanation for this result [ 95 ]. In sum, α-synuclein deposition and loss of dopaminergic neurons have a crucial role in PD-related pathological changes, and both are contributing factors to the disruption of the sleep cycle and the circadian rhythm [ 79 ].…”

Lymphatic system in the brain

“…Association of the disturbed glymphatic system in PD is proved in diffusion tensor image analysis along with the perivascular space (DTI-ALPS) method where PD exerts a prominent reduction in ALPS index [ 12 ]. Sleep disturbance is characteristic of PD causing oxidative stress and metabolic waste( α -synuclein) accumulation [ 10 ]. There is an interrelation between pain and glymphatic system due to the presence of norepinephrine [ 15 ].…”