Awakening dormant dopaminergic neurons is key to reversing Parkinson's, say researchers
Parkinson's disease affects as many as 10 million people across the world and apart from causing just movement disabilities. It also adversely impacts their quality of life. The current treatment approaches for Parkinson's disease (PD) are mostly symptomatic, giving little emphasis on reversing its debilitating effects.ANI | Seoul | Updated: 11-01-2020 20:18 IST | Created: 11-01-2020 20:18 IST
Parkinson's disease affects as many as 10 million people across the world and apart from causing just movement disabilities. It also adversely impacts their quality of life. The current treatment approaches for Parkinson's disease (PD) are mostly symptomatic, giving little emphasis on reversing its debilitating effects. Going by the existing body of knowledge, movements abnormalities of PD begin in the brain where the production of dopamine, a neurotransmitter for movement control, is irreversibly impaired, as a consequence neuronal death.
Currently, L-DOPA, a potent PD medication is mainly prescribed to replenish dopamine in the deprived brain. However, such a treatment is only symptomatic, rather than a disease-modifying therapy. Long-term use of L-DOPA is 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 of the Institute for Basic Science (IBS), Korea Institute of Science and Technology (KIST), and Asan Medical Center (AMC) respectively, 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 till 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 synthesise 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 the roles of other neuronal activities, such as surrounding astrocytes," says Dr 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." The researchers observed when the number of astrocyte cells 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 blocks astrocytic GABA synthesis. The awakening of dormant dopaminergic neurons leads to significant alleviation of PD motor symptoms.
They also used optogenetic tools that use light to control genetically modified neurons, to inhibit dopaminergic neurons of normal rats, inducing Parkinsonian motor deficits. They also demonstrated that activating the dormant dopaminergic neurons by the 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," says 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."
The researchers also suggest that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD, especially in the early stages of PD in which non-functional yet live dopaminergic neurons are waiting to be awakened. (ANI)
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