Chronic lack of sleep and irregular sleep-wake cycles may be
risk factors of Parkinson's disease, new work by researchers at the Lewis Katz
School of Medicine at Temple University (LKSOM) suggests. In an animal model,
the researchers show that disturbances in circadian rhythm that exist before
Parkinson's onset dramatically worsen motor and learning deficits brought on by
the disease.
The new work, led by Domenico Praticò, MD, Professor in the
Departments of Pharmacology and Microbiology and the Center for Translational
Medicine at LKSOM, is the first to demonstrate that an environmental factor -
chronic daily exposure to long periods of light with brief exposure to dark,
which alters circadian rhythm - can exacerbate Parkinson's symptoms and
pathology. The findings appear online April 5 in the journal Molecular
Psychiatry.
Patients with Parkinson's disease often suffer from recurrent
sleep disorders and disturbances in circadian rhythm, the roughly 24-hour
biological cycle of humans. But whether those disturbances impact the
development and progression of Parkinson's has been unclear. "Many think
that sleep disturbances are secondary to Parkinson's disease," Dr. Praticò
explained. "But circadian rhythm disturbances are increasingly reported
before the onset of Parkinson's, suggesting that they could be risk factors."
After age 60, the majority of Parkinson's disease cases are
idiopathic, their cause unknown. According to Dr. Praticò, it is probable that
in those cases, the disease arises as a result of interactions between genes
and environmental risk factors. The latter include chronic stress, sleep
disorders, and circadian disturbances, all of which affect the function of the
central nervous system, potentially contributing to the pathology that
characterizes Parkinson's disease.
Dr. Praticò and colleagues investigated the role of altered
circadian rhythm using a well-established mouse model of Parkinson's disease,
in which treatment with MPTP, a neurotoxin, reproduces aspects of the disease
in mice. The researchers divided animals into two groups.
The first, the control group, was maintained on a regular
circadian schedule, being exposed to 12 hours of light followed by 12 hours of
dark each day. In the second group, circadian rhythm was altered through daily
exposure to 20 hours of light followed by just four hours of dark. After 60
days, some animals from each group were treated with MPTP.
Assessments of movement and behavior showed that all mice
treated with MPTP developed Parkinson's disease, but animals with altered
circadian rhythm experienced significant learning impairments. They also
exhibited severe motor deficits, with drastic reductions in motor coordination
and motor learning skills - far worse than the deficits observed in
MPTP-treated mice with normal circadian rhythm.
To understand why circadian rhythm disturbance worsens
Parkinson's disease, Dr. Praticò and his team examined the brains of affected
mice. In a region known as the substantia nigra, they observed significant
reductions in neurons that produce dopamine, the loss of which is a major
molecular feature of Parkinson's disease. "The substantia nigra is the
epicenter of Parkinson's disease," Dr. Praticò said. "Cells normally
die in that region of the brain, but our study shows that circadian rhythm
disturbance accelerates cell death there."
In addition, cells known as microglia, which normally protect
neurons, were superactive in circadian-disrupted MPTP-treated mice. The
overactivation of microglia can actually worsen neuroinflammation and
potentially speed the progression of Parkinson's disease.
The next challenge is to see if the findings can be replicated
in other animal models. "If those studies are successful, we'll then try
to reestablish normal circadian rhythm in circadian-disrupted animals to
explore the possibility of reversing brain inflammation and cell death,"
Dr. Praticò said.
The outcomes of those studies could have important implications
for the prevention and treatment of Parkinson's disease in persons with chronic
sleep disorders.
Source:
Temple University Health System
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