As
many as seven to 10 million people in the world are thought to live with
Parkinson's disease (PD). Being the second most common neurodegenerative
disease, PD severely affects patients' quality of life, not just brining
movement abnormalities. Despite its prevalence and negative impact, current
medical treatments for PD rely on alleviating PD symptoms with little efforts
to explore ways to reverse the symptoms.
It is
firmly believed that abnormal movements of PD begin in the brain where the
production of dopamine, a neurotransmitter for movement control, is
irreversibly impaired, i.e. in a state of neuronal death. Currently, L-DOPA, a
potent PD medication is mainly prescribed to replenish dopamine in the deprived
brain. However, such a treatment is symptomatic therapy, rather than a
disease-modifying therapy. Long-term use of L-DOPA is well-known to cause
serious side effects such as involuntary, erratic, and writhing movements.
Led by
Dr. C. Justin Lee along with Dr. Hoon Ryu and Dr. Sang Ryong Jeon, researchers
at the Center for Cognition and Sociality within the Institute for Basic
Science (IBS), Korea Institute of Science and Technology (KIST), and Asan
Medical Center (AMC) have discovered a new mechanism for PD pathology. The
researchers reported that the symptoms of PD begin when dopaminergic neurons
are "non-functional," even before they die off. Though the neuronal
death had been until now believed to be the obvious cause of PD, the study
found that the movement abnormalities of PD begin in the earlier stage when
dopaminergic neurons, though being alive, cannot synthesize dopamine (in a
dormant state).
"Everyone
has been so trapped in the conventional idea of the neuronal death as the
single cause of PD. That hampers efforts to investigate roles of other neuronal
activities, such as surrounding astrocytes," said Dr. C. Justin Lee, the
corresponding author of the study. Lee adds, "The neuronal death ruled out
any possibility to reverse PD. Since dormant neurons can be awakened to resume
their production capability, this finding will allow us to give PD patients
hope to live a new life without PD."
The
researchers observed when the number of astrocytes abnormally increases due to
the destruction of nearby neurons, GABA, an inhibitory neurotransmitter is
released in the brains of both animal PD models and human patients in an
excessive amount. This excessive output of GABA suppresses dopaminergic
neurons, putting the production of dopamine on a hold. Notably, they confirmed
that the dormant dopaminergic neurons are alive with the existence of DOPA
decarboxylase. Furthermore, they revealed that these neurons could be awakened
by treatment with MAO-B inhibitors, which block astrocytic GABA synthesis. The
awakening of dormant dopaminergic neurons leads to a significant alleviation of
PD motor symptoms.
The
researchers also used optogenetic tools to inhibit dopaminergic neurons of
normal rats, inducing Parkinsonian motor deficits. They also demonstrated that
activating the dormant dopaminergic neurons by optogenetic treatment can
alleviate PD motor symptoms. "This research refutes the common belief that
there is no disease-modifying treatment for PD due to its basis on neuronal
cell death," said Dr. Hoon Ryu of Brain Science Institute at KIST.
"The significance of this study lies in its potential as the new form of
treatment for patients in early stages of PD."
Dr.
Sang Ryong Jeon of AMC explained, "So far, it had been firmly believed
that idiopathic PD is caused by the death of dopaminergic neurons in substantia
nigra. However, this research demonstrates that functional inhibition of
dopaminergic neurons by surrounding astrocytes is the core cause of PD. It
should be a drastic turning point in understanding and treating PD, and
possibly other neurodegenerative disease as well."
With
this study, the researchers suggest that disinhibiting dormant dopaminergic
neurons by blocking excessive astrocytic GABA could be an effective therapeutic
strategy against PD, especially in early stages of PD in which non-functional
yet live dopaminergic neurons are waiting to be awaken.
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