Validation of Period1 as a Therapeutic Target to Improve Sleep and Circadian Dysfunction in Parkinson’s Disease

Project Summary

Evaluate if improved sleep and circadian rhythms resynchronization can protect against neuropathological features associated with sleep dysfunction in experimental PD models. Collectively, these studies will validate Per1 as a potential disease-modifying target for PD and enable the development of novel therapeutic approaches to improve sleep and circadian function in PD.

Principal Investigator

Oliver Rawashdeh, PhD

Study Rationale

Mounting evidence suggests Parkinson’s disease patients have accumulating disruption of sleep and circadian (24-hourly) rhythms which are thought to worsen other symptoms associated with PD. We have recently discovered a new pathway called Period1 (Per1) which can regulate the sensitivity of the biological clock to light. Removal or blocking of this pathway enhance the responsiveness to light which is affected in PD. This in turn can increase the consistency by which light regulates sleep and thereby rapidly restore biological rhythms and stabilize sleep patterns that are disrupted in PD patients.

Hypothesis

Our studies will evaluate if the improved sleep quality and biological clock (circadian) functions we have discovered in mice lacking the Per1 pathway can prevent or reduce key features of PD pathology and the progression of the disease progression in animal models.

Study Design

Our research to date has confirmed that mice lacking the Per1 pathway have dramatically improved sleep quality and biological clock regulation. Therefore, we will determine if healthy sleep parameters, sleep quality and the integrity of biological clocks are maintained in experimental animal models of PD which lack the Per1 pathway. We will also confirm if the benefits in sleep quality and biological clock sensitivity we see in the absence of the Per1 pathway, can lead to a reduction in brain inflammation, alpha synuclein accumulation and ultimately the death of brain cells which produce dopamine.

Impact on Diagnosis/Treatment of Parkinson’s disease

Our studies will confirm an exciting new role for the biological clock regulator Per1 in PD. They will also confirm whether blocking or reducing Per1 could be a viable disease-modifying approach to improve sleep quality and restore overall circadian dysregulation which occurs in PD and thereby reduce motor and non-motor symptoms affect by disruption of sleep and biological rhythms.

Next Steps for Development

We are currently developing Per1 reporters for screening new drugs. Our studies will confirm if a Per1 is a good target for future drug development. Our research also has direct implications for other treatments, such as light therapy, which are being developed to restore sleep disruption in PD.