Rethinking the Link between Parkinson’s Disease and Circadian Rhythm Disorders

By: Tiffany Parnell
Thursday, September 1, 2016

Circadian rhythm disorders, such as irregular sleep-wake rhythms, are hallmarks of Parkinson’s disease. The medical community has traditionally believed the disorders are a side effect of Parkinson’s, but a recently published study is challenging that view.

In as many as 90 percent of cases, Parkinson’s disease is classified as idiopathic, according to the National Parkinson Foundation. A combination of environmental risk factors, including traumatic head injuries and exposure to pesticides and heavy metals, as well as genetic predisposition, are suspected of playing a role in these cases.

“[M]ost people who are exposed to various toxins [are] not going to develop Parkinson’s disease,” says James Beck, PhD, Vice President of Scientific Affairs at the Parkinson’s Disease Foundation. “That’s why we think there’s a genetic component, as well, that may prime the body so that when someone is exposed to environmental insult — whether it be some type of pesticide or toxin or a head injury — [it] may then activate or trigger something that’s genetically susceptible in that individual that can lead to Parkinson’s disease.”

Researchers involved in a recently published Molecular Psychiatry study believe an additional environmental risk factor should be added to the list: circadian rhythm disruption.

Secondary Symptom or Functional Role?

To investigate whether circadian rhythm disorders are a disease side effect or may actually contribute to the pathogenesis of Parkinson’s disease, researchers evaluated the effect of circadian rhythm disruption in mice with induced parkinsonism. A group of 6-month-old mice was split into a control group and a circadian disruption (CD) group. Mice in the control group experienced a normal circadian schedule consisting of 12 hours of light and 12 hours of darkness. Mice in the CD group were exposed to four hours of darkness and 20 hours of light. After following these schedules for 60 days, researchers used a well-established animal model of Parkinson’s disease, in which the neurotoxin MPTP is administered to induce parkinsonism in both groups.

“MPTP [has been] known for more than 20 years to be a selective toxin for cells in the substantia nigra, the area of the brain that is damaged in an individual with Parkinson’s disease,” says study lead author Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and at the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University. “If you inject a mouse with MPTP, you specially and selectively damage this area, which is the one responsible for the disease.”

A week after MPTP administration, researchers observed how parkinsonism manifested in the two groups of mice.

“The mice that underwent circadian disruption displayed extreme muscle weakness, akinesia, less stable gait posture, exaggerated motor deficits and impairment of the acquisition of motor skills compared to the mice that were exposed to the regular light/dark cycle,” says Elisabetta Lauretti, a PhD student at the Lewis Katz School of Medicine and first author of the Molecular Psychiatry paper.

Variations in parkinsonism presentation between the CD mice and mice in the control group were also observed on an anatomical level. Mice exposed to CD had a 30 percent higher rate of cell death in the substantia nigra than mice in the control group. In CD mice, researchers also noted higher activation rates of astrocytes — glial cells that play a role in brain homeostasis and, when activated, help regulate brain inflammation and release immune mediators that can exhibit both neuroprotective and neurotoxic effects, according to a study in Dialogues in Clinical Neuroscience.

“The evidence from our study suggests that the disruption of this rhythm in some ways alters the homeostatic function of inflammatory cells and astrocytes,” Dr. Praticò says. “We believe that the cell biology of the astrocytes is connected with circadian variation, and we believe this alteration can send the wrong message to the astrocytes.”

Avenues for Further Investigation

This is not the first study to measure circadian rhythms in animals with induced parkinsonism, but it is the first to disrupt circadian rhythm dysfunction prior to induction. Study results support the hypothesis that sleep disorders are an early event in Parkinson’s disease development and may be considered a risk factor for the condition instead of a secondary symptom, according to Lauretti. The study also suggests circadian rhythm disruption may speed disease progression and contribute to more severe movement-related and cognitive impairments. Before definitive conclusions are reached, however, further study is needed.

“In any research study, one important thing is to reproduce the same results using a different model,” Dr. Praticò says. “... What we are doing now is using a genetic model of Parkinson’s disease to see if we can reproduce the same results.”