There is nothing more terrifying than losing control of your own body and mind.While it may be difficult to imagine such a thing happening, this loss of control is the bitter reality for those suffering from Parkinson’s disease— a progressive neurodegenerative disease that oftentimes has no definite cause and has little to do to a person’s health before onset.
Researchers and medical professionals have tried to identify the causes of Parkison’s and develop effective treatments, yet these attempts have been largely fruitless.
Clinically, Parkinson’s is characterized by the widespread death of dopamine-producing cells in the substantia nigra, a region crucial for regulating and modulating movement, reward, and executive functions. Parkinson’s Disease is also associated with an excessive amount of alpha-synuclein, a protein involved in neuron signaling and neurotransmitter release.
The primary symptoms include executive dysfunction, uncoordinated and limited movement, psychosis, and depression. Parkinson’s researchers have put forward a number of explanations, or rather, risk factors for the development of the disease, such as oxidative stress, exposure to chemical agents like manganese ions and the pesticide paraquat, as well as hereditary predispositions and traumatic head injuries.
Though these factors have been linked to the onset of Parkison’s, none of them can decisively predict the disease.
In the 1960s, the fight against Parkinson’s saw a bright first step with the development of L-dopa, a chemical precursor to dopamine, the key neurotransmitter absent in those afflicted. Initial trials for L-dopa showed great promise, and the drug is still used today in managing Parkinson’s, whose prior treatments consisted mostly of supportive and palliative care or perplexing surgical techniques.
However, L-dopa is far from perfect, and continued use more often than not leads to various complications, some of which are just as hard to manage as Parkinson’s itself.
The dopamine analogue drugs that were introduced following L-dopa. were also found to create a variety of unpleasant and unpredictable side effects.
The field of Parkinson’s research is long overdue for a step forward, and researchers at the University of Copenhagen have put forth the effort in that direction.
During normal signaling and brain function, cells in the brain’s substantia nigra produce dopamine, which is then transported to the pedunculopontine nucleus (PPN), a command center containing glutamatergic neurons responsible for maintaining and executing locomotor functions.
In Parkinson’s, the cell death in the basal ganglia severs this chain of communication, with the PPN unable to receive the necessary neurotransmitters to carry out its functions. Based on this observation, the aforementioned surgical techniques relied on using deep brain stimulation (DBS) to stimulate the PPN, which led to mixed results.
The Copenhagen study, however, delved deeper into the PPN than just stimulating the PPN by identifying the three crucial cell types that comprise it: GABAergic, cholinergic, and glutamatergic cells.
Using techniques drawing from earlier DBS methodology, the researchers identified that mice with Parkinson’s disease demonstrated measurable improvement in locomotor functions when subjected to a highly specific type of DBS that targeted glutamatergic excitatory neurons in the caudal region of the PPN.
These mice, previously stumbling constantly and unable to maintain their balance, were able to walk with restored balance and speed following treatment while showing no symptoms of Parkinson’s.
The improvement in this novel and high-precision procedure was never seen in older methods of DBS, which are never able to fully restore all aspects of locomotor functionality.
“We use a technology to target specific groups of cells in the PPN in order to close in on what areas are the best to stimulate, if we want to alleviate these particular symptoms. The result shows that the motor improvement is optimal, if we stimulate what we call excitatory neurons in the caudal area of the PPN,” Ole Khein, PhD, a Professor of Integrative Neuroscience at the University of Copenhagen, explained in a press release.
“We believe that clinical trials with brainstem DBS are the right strategy to facilitate patients to walk properly again. But the variable clinical results occur, because DBS would require higher precision to target the particular group of neurons in the caudal PPN. It is a very delicate area, because if we were to stimulate excitatory neurons in other areas than the caudal PPN, it would cause complete immobilization instead,” added Khein.
Overall, the researchers behind this project believe that their findings can serve as the base for a new approach to treating Parkinson’s, albeit with significantly more research and familiarization with the mechanisms behind the disease.
“We believe that clinical trials with brainstem DBS are the right strategy to facilitate patients to walk properly again. But the variable clinical results occur, because DBS would require higher precision to target the particular group of neurons in the caudal PPN,” Debora Masini, PhD, a postdoctoral researcher at the Department of Neuroscience and Pharmacology at the University of Copenhagen, said. “We systematically compared stimulation of different locations and cell types in a series of complementary experiments. And they all pointed towards the same conclusion. It strongly indicates these excitatory neurons in the caudal PPN are an ideal target for recovery of movement loss,” she added, defining her vision for the focus that future research on Parkinson’s should follow.
Parkinson’s has been a longstanding challenge for medical researchers, but the work done by these researchers demonstrates an optimistic step forward and drive to think innovatively while drawing on what we’ve learned in the past.
~ Dimitri Lin ’25
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