• Date: July 22, 2020

“You have Parkinson’s.” More and more people are having to hear these words. In 2015 there were 6 million people with the disease and this figure is expected to double by 2040. The reason behind this growth is the aging population. Many people dream of living longer, but doing so in good health is just as important, if not more so.

Because of this, World Brain Day this year is dedicated to Parkinson’s. We are also taking part in this international campaign by focusing on research. We spoke to three scientists who are investigating new therapeutic approaches that could potentially treat and even prevent this devastating disease in the future. All three of them are doing it with support from the ”la Caixa” Foundation.

The microbiome, the connection between the gut and the brain

Over the last decade, the study of the make-up of the bacteria that live in our digestive tract and how they interact with our bodily functions is providing answers to understand a huge number of diseases. Ariadna Laguna, researcher at the Vall d’Hebron Research Institute (VHIR) and awardee of a post-doctoral Junior Leader fellowship from the “la Caixa” Foundation, is heading up a project that aims to shed light on how interactions between the microbiome and the brain can affect the onset and development of Parkinson’s.

Ariadna Laguna in her laboratory. Credit: Núria Peñuelas (VHIR)

“There are studies that show that the make-up of the gut microbiota is determined when we are born, through vaginal delivery. However, the make-up of the microbiota is very dynamic and changes throughout our adult lives and during ageing, influenced by an infinite range of factors”, said Laguna. Regarding Parkinson’s patients, a specific alteration has been discovered, although it is unclear as to whether it could contribute towards the origin of the neurodegeneration involved in the disease or if it is the condition that causes these changes. “One of the goals of our project is to understand what comes first, the changes to the brain or to the microbiota.”

As of now, Laguna works with animal models and, as such, she does not think treatment will be ready in the short-term. “We need longitudinal studies that would allow us to monitor healthy people and also people at risk of suffering from Parkinson’s to see how the make-up of the microbiome develops in both groups. This will allow us to identify biomarkers to detect people who have a higher risk of developing the disease. If we manage to do this in the early stages, we might be able to treat them with effective therapy to prevent or delay the appearance of Parkinson’s” said Laguna.

Although we still have a lot to learn about two-way communication between the brain and the gut, we now know that this is a key element in other neurodegenerative diseases and also in autism spectrum disorders, schizophrenia and depression. As such, this is a very promising line of investigation for improving people’s long-term brain health.

Alpha-synuclein, the protein responsible for toxin aggregation

Salvador Ventura, researcher at the Institute of Biotechnology and Biomedicine (IBB) at the Autonomous University of Barcelona, is leading a CaixaImpulse project to tackle Parkinson’s. His team has found a molecule that could turn back the accumulation of toxic aggregates in neurons, one of the main characteristics of neurodegenerative diseases.”

Salvador Ventura. Credit: IBB.

“This phenomenon is common in pathologies such as Alzheimer’s and Huntington's disease, but in each of these diseases there is a different protein forming the aggregates. In Parkinson's, it is alpha-synuclein and it accumulates mostly in dopaminergic neurons in the substantia nigra of the midbrain, causing the motor issue we are all aware of”, said Ventura.

His team has tested 14,400 different molecules to see if any of them is able to attach itself to alpha-synuclein and inhibit its neurotoxic action. “It wasn’t easy”, said Ventura, “because alpha-synuclein does not have a defined structure. It is like a thread that is constantly moving; its structure changes each millisecond. After two years of tests, we selected 30 molecules that we have described exhaustively. Out of these 30, we narrowed them down to 6, and lastly to SynuClean-D, which we are developing to test its effectiveness in animals and, if the results are positive, we’ll see if we can run clinical trials.”

SynuClean-D prevents the aggregation of the alpha-synuclein protein and also reverts the existing aggregates. What is more, it can prevent the propagation of the disease: “Although it starts in the substantia nigra, the pathology spreads through the brain. Toxic aggregates pass from neuron to neuron, transforming healthy proteins into diseased proteins. SynuClean-D can inhibit this transmission in vitro”, said Ventura.

Synaptic connections, key elements in neurodegeneration

Other features that neurodegenerative diseases share is the loss of connections between neurons, which leads to neuron death. Alicia Mansilla, a researcher at the Ramón y Cajal University Hospital, is leading another CaixaImpulse project aimed at identifying molecules that can preserve and regenerate these connections in order to save neurons from death or at least slow down the process.

Alicia Mansilla. Credit: ”la Caixa” Foundation

“We are developing small molecules to treat neurodegenerative diseases. At the moment, we are looking into how they work and what their action mechanism is” said Mansilla. “We hope that soon we will come up with medications, some kind of treatment, that would allow us to treat diseases that, as of yet, have no cure.”

The molecules that Mansilla’s team designed are aimed at stabilising the bond between two proteins—neuronal calcium sensor (NCS-1) and the guanine exchange factor (Ric8a)—involved in setting the amount and activity of neuronal connections. Since this is a general target and not a specific one for a certain disease, in future it will allow them to treat not only Parkinson's, but also other conditions such as Alzheimer’s and Huntington's disease, increasing the number and effectiveness of lost neuronal connections.

One of these molecules has been shown to have great potential in cell models and animals (Drosophila melanogaster) and they are now working on mouse models. “We want to get it out of the lab and to the patients”, said Mansilla. She also stressed the need for collaboration from industry and the support received through the CaixaImpulse fellowship to achieve the goal of turning laboratory investigation into effective treatments that reach those who need them most.

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October 19, 2020

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