Peripheral Clock System Abnormalities in Patients With Parkinson’s Disease

Objective: To evaluate the altered expression of peripheral clock genes, circulating melatonin levels, and their correlations with sleep-wake phenotypes including probable rapid eye movement sleep behavior disorder (pRBD) symptoms in a relatively large population of Parkinson’s disease (PD) patients. Methods: We determined the expression profiles of five principal clock genes, BMAL1 , CLOCK , CRY1 , PER1 , and PER2 , in the peripheral blood mononuclear cells (PBMCs) of PD patients ( n = 326), and healthy controls (HC, n = 314) using quantitative real-time PCR. Melatonin concentration in the plasma of two groups was evaluated by enzyme-linked immunosorbent assay. Then we performed comprehensive association analyses on the PBMCs clock gene expression, plasma melatonin levels and sleep characteristics. Results: Our data showed that the expression levels of BMAL1 , CLOCK , CRY1 , PER1 , and PER2 were significantly decreased in the PBMCs of PD as compared with that of HC ( P < 0.05). PD patients had reduced plasma melatonin levels compared with HC ( P < 0.0001). pRBD and excessive daytime sleepiness are common in these PD patients and are associated with the expression levels of all five clock genes ( r = −0.344∼−0.789, P < 0.01) and melatonin concentration ( r = −0.509∼−0.753, P < 0.01). Statistical analyses also revealed that a combination of five clock genes and melatonin could reach a high diagnostic performance (areas under the curves, 97%) for PD comorbid pRBD. Conclusion: This case-control study demonstrates that peripheral BMAL1 , CLOCK , CRY1 , PER1, PER2 , and melatonin levels are altered in PD patients and may serve as endogenous markers for sleep and wakefulness disturbances of PD.