Parkinson's disease: The new investigation before the new surgery

 At the Gulbenkian Institute of Molecular Medicine, neuroscientist Luísa Lopes is developing a project for a new surgical approach to treating Parkinson's disease.

Parkinson's disease was first described more than two hundred years ago. In 1817, in the essay An Essay on the Shaking Palsy, the English doctor James Parkinson (1755-1824) described some of the most typical motor symptoms of this disease: tremors, muscle rigidity, slowness of movement and loss of balance.

But only recently, with the progress of neuroscience, has it been possible to understand what leads to all these symptoms: the death of neurons in an area of ​​the brain called the substantia nigra of the midbrain. These neurons are responsible for the production of dopamine, the neurotransmitter that powers the brain structures that control movements. Without dopamine, difficulties arise.

Currently, this is the second most common neurodegenerative disease in the world population, behind only Alzheimer's disease. The World Health Organization estimates that it affects around one percent of the population over 65 years of age. In Portugal, according to data from 2017, it is estimated that there are between 18 and 20 thousand people with this diagnosis.

Despite being known for a long time, the disease is still incurable. However, there are two main ways to treat it, to try to control the symptoms: with various types of medications to increase the levels or action of dopamine, and when these do not work or cause many side effects, deep brain stimulation (DBS) ), a surgical procedure in which electrodes are implanted in specific areas of the brain to send controlled electrical impulses in order to regulate abnormal brain activity and lessen symptoms

The surgery is complex and can take eight to nine hours”, says Luísa Lopes, researcher at the Gulbenkian Institute of Molecular Medicine (GIMM). “This means that many people, whether due to [advanced] age or having other illnesses, are not eligible to do so.” In other words, despite good efficacy rates in controlling many of the symptoms, not all patients have the criteria to access treatment — which also sometimes involves post-operative complications, such as infections of the implanted material, which require reversal. the entire procedure

All these concerns reached the neuroscientist through someone who deals with them daily: neurosurgeon Pedro Duarte Baptista, from Hospital de Santa Maria, who is part of a team that operates and monitors these patients in consultation. “I do pre-clinical research, but we collaborate with the neurosurgery team at Hospital de Santa Maria and this project was based on the difficulties they experience”, says the researcher.

Together, the question arose: “What if we could stimulate the brain in another way, so as to increase the effectiveness and number of people eligible for surgery?” And that is precisely what they are trying to do using, at this early stage, animal models.

The idea is to use a relatively new tool, luminopsins. These proteins are introduced into groups of specific neurons through a genetically modified virus (harmless, used as a form of transport) and create artificial channels, which function as doors. In this project, the innovative idea is to combine the use of luminopsins with a chemical molecule, which is administered to the patient intravenously or orally, which basically activates this port. “The channel created by luminopsin remains there, inert, after the injection is administered. Only when the animal ingests the chemical substance does the channel 'open': the ions enter and the neuron remains active. The viral injection that establishes this artificial channel is relatively simple and takes little time. “Which means that patients who cannot undergo a complicated surgical procedure are not excluded”, explains Luísa Lopes.

Furthermore, the patient would not need to have anything implanted in the body, as is the case now, which also eliminates the possibility of post-operative infections and which means that if the treatment for some reason does not work, there is no need for another procedure to remove implanted material. Furthermore, it is possible that it will allow for much greater precision in the neurons that are stimulated.

To test everything from the viral injection to the chemical compound, simple animal models, namely mice, are being used. If everything goes well, the team will have to repeat and adjust all the tests, in a second phase, still with mice and, only then, there is the possibility of clinical tests on non-human primates. This means that there are still, at this point, many years of clinical trials ahead before this solution, if effective, reaches clinical practice.

But this is just one of the many projects that are underway in the laboratory that Luísa Lopes directs, at GIMM, where she studies the neurobiology of aging and disease: over the last decades she has studied topics as different as dementia, sleep, memory and the effects of chronic stress on our brain.

When asked about her academic career, the 49-year-old scientist usually says that “she is the result of a public school in the outskirts, with great pride”. After high school, he graduated in Biochemistry at the Faculty of Sciences of Lisbon and completed his final internship in the area of ​​neurophysiology, studying the effects of a receptor — adenosine — on aging.

At that time, in the early 2000s, there was still little research in the area of ​​neurosciences in Portugal. Therefore, he completed a doctorate between the University of Cambridge, in the United Kingdom, and the Karolinska Institute, in Sweden. He completed his academic career with a post-doctorate in Switzerland: Nestlé was looking, for the first time, to hire a neuroscientist to better understand the gut-brain interaction, which was still largely unexplored. He stayed there for three years, before returning to Portugal in 2007, starting to work at the Institute of Molecular Medicine (currently GIMM), with a project in which he investigated the relationship between chronic stress and dementia, using animal models.

Decades after starting to study cognitive aging — and having already studied so many different aspects — one of the things that impressed the scientist most was realizing that there is no need for a loss of neurons to cause cognitive decline: subtle changes in the functioning of synapses are enough. , the connections between neurons. “Small synaptic dysfunction is enough to impact cognitive function, even when brain structure appears normal.”

In his laboratory, studies of premature aging in animals have revealed that factors such as inflammation, stress and circadian dysfunction can cause these changes in synapses, long before atrophy or loss of neurons is noticed. “These are changes that we are unable to measure in humans this early, but we know they can be crucial to intervening before the damage is irreversible.”

That is why, for the researcher, the priority must be clear: avoid these early changes. “When the dysfunction is only synaptic, it is still reversible. The loss of neurons causes irreversible cognitive decline.” And, knowing that some of these synaptic changes are associated with anxiety and sleep — or the lack thereof, Luísa Lopes has made an effort to carry out scientific dissemination work in this area, both in the general community and particularly in companies. “We need to combat this false idea, but still very present in our culture, that it is good to always be active, present and available.”

For Luísa, balance begins at home – or, in this case, in the laboratory. He recognizes that research ends up shaping daily choices and the way he works as a team. A striking example came when he began to study chronotypes, the biological rhythms that determine the times of day when each person is most awake and productive. “I'm very morning person. Having a meeting at eight in the morning doesn’t cost me anything, but not everyone works like that.”

In his laboratory, which usually has around ten people, the individual chronotypes of all elements were studied and the time for team meetings was adjusted to a period aligned with everyone's peak productivity: 10am. “It’s small details that make all the difference. People get more tired when they are working counterclockwise, the work pays less and, in the long term, this can have an impact on health, particularly mental health.”

This article is part of a series on cutting-edge scientific research and is a partnership between Observador, the “la Caixa” Foundation and BPI. The project led by Luísa Lopes, from GIMM, was one of six selected for financing (the researcher received fifty thousand euros) by the foundation based in Barcelona, ​​under the 2023 edition of CaixaImpulse Innovation in Health, a program that promotes the transformation of knowledge scientific created in research centers, universities and hospitals in companies and products that generate value for society. Registration for the 2025 edition is now open.