Recent Progress in Non-motor Features of Parkinson's Disease with a Focus on Circadian Rhythm Dysregulation

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.

Keywords: Circadian rhythm dysregulation; Circadian rhythm gene; Dopamine; Parkinson’s disease; REM sleep behavior disorder.

Fig. 1

Dysregulated circadian rhythm network in Parkinson’s disease. Circadian rhythm genes interact with each other to form a complex network. The Clock/Bmal1 heterodimer activates Per and Tim gene expression, and the Per and Tim proteins form heterodimers. Per, Tim, or Per/Tim heterodimer restrains Clock and Bmal1 activity and their transcription. The Clock/Bmal1 heterodimer activates Per and Cry gene expression to form heterodimers. Once Per and Cry proteins accumulate to a certain extent, they form complexes with Bmal1/Clock heterodimers, and inhibit their own transcription. Then, the Per/Cry inhibitory complex degrades into the next cycle. NPAS2 mediates Bmal1 expression via the acid-related orphan receptor RORα and Rev-erbα, and further regulates the activity of Clock/Baml1 heterodimers. These receptors bind with retinoic acid-related orphan nuclear receptor response elements, which are located in the Bmal1 promoter, activate Bmal1 transcription through RORs and inhibit Bmal1 transcription through Rev-erbs. Circadian rhythm dysregulation may impact PD through the induction of neuroinflammation, impaired protein homeostasis, and redox homeostasis, manifested by various non-motor symptoms including sleep disorders such as RBD, RLS, EDS, sundown syndrome, BP rhythm disorders, CBT rhythm disorders, HRV rhythm disorders, neuroendocrine function dysregulation, and GI dysfunction. RBD rapid eye movement sleep behavior disorder, BP blood pressure, CBT core-body temperature, HRV Heart rate variability, RLS restless leg syndrome, EDS excessive daytime sleepiness, GI gastrointestinal.

Fig. 2

Circadian rhythm genes and Parkinson’s disease. Circadian rhythm genes participate in PD pathology via various pathways. The Clock/Cry complex activates Tim and Per expression to form complexes and inhibits Clock/Cry complex activity. This network interacts with ATG5 to regulate autophagy in PD. Clock acetylates Bmal1, and inhibits the Bmal1/Clock-dependent transcription of Per2. SIRT1 deacetylates Per2 and Bmal1. This network along with melatonin interacts with antioxidant enzymes yielding an antioxidative response in PD. Bmal1 and Clock are lower in PD and the Bmal1/Clock complex-dependent transcription of Per1, Per2, Dbp, and Rev-erbα is inhibited. This network activates microglia-dependent neuroinflammation in PD. Rev-erbα competitively cooperates with Nurr1 to control DA gene transcription and the development and function of DA neurons. Some HSF1 targets that are associate with circadian rhythm genes (RXRA, Bhlhe40, and DBP) are upregulated, while some others (Bmal1) are inhibited. Non-coding RNAs undertake epigenetic regulation of the circadian rhythm system, but the mechanism is not clear. Circadian rhythm alterations, including abnormal expression of circadian rhythm genes, epigenetic changes, and gene polymorphisms, participate in the pathogenesis of PD.