Cambridge researchers building better tests for Parkinson’s

Professor Sir David Klenerman is a researcher based at the University of Cambridge. Some of his most celebrated research includes revolutionising the ability to sequence DNA on a much larger and faster scale than previously possible. His more recent work focuses on studying how clumps of protein, called protein aggregates, develop in brain cells of people with neurological conditions, such as Parkinson’s and Alzheimer’s.

Between 2020 and 2024, Parkinson’s UK granted over £270,000 to a project, led by Professor Klenerman, to study clumps of protein found in the brains of people with Parkinson’s. The study involved using a very sensitive method to see tiny protein aggregates under the microscope, with the aim of better understanding the role they may play in the development of the condition.

Read the published paper in the journal Brain

We caught up with Professor David Klenerman, and 2 senior members of his research team, postdoctoral researchers, Dr Yu Zhang and Dr Evgeniia Lobanova. Currently, they are working to understand more about the different proteins linked to neurological conditions, and how these proteins change over time in different conditions. The ultimate goal is to develop a test that could one day diagnose conditions such as Parkinson’s and Alzheimer’s, and even detect the conditions much earlier than currently possible.

What is a protein?

Proteins are the building blocks of the cells. They each have a role, from enzymes that break down the food we eat, to structural proteins that make up our skin and hair. For reasons unknown, some proteins can become ‘sticky’, start to clump together, and cause problems in the brain. One such protein is called alpha-synuclein.

David: “Alpha-synuclein is a protein that is expressed in cells in the brain, particularly at the place where brain cells communicate with each other, known as the synapse.

“It’s been known for a long time that alpha-synuclein can clump together and produce protein aggregates called Lewy bodies. This is one of the key things that you find in the brains of people who have Parkinson’s. Therefore, researchers think that the aggregation of alpha-synuclein into these clumps is a key process in the development of the condition. One of the key things we have found is that there is a whole range of protein aggregates of different sizes, and that the number or size of these aggregates were different between people who developed Parkinson’s and those who didn’t.

“The process starts with a single protein, which comes together with another one to form 2, and then 2 becomes 3 etc. And then these small clumps can start to stick together, ending up with bigger clumps of alpha-synuclein in the brain. Our most surprising result was that you could see these protein clumps in the blood as well as the cerebrospinal fluid, which is fluid that surrounds the brain and spinal cord.

“Our work is around the idea that if we are seeing very small clumps in samples, it might be an indicator that the person is on their way to forming the bigger clumps in the brain, and possibly are in the early stages of developing Parkinson’s.”

How does the lab group work together?

Dr Yu Zhang joined Professor Klenerman’s laboratory as a PhD student in 2020. Now a postdoctorate, Yu brings his background in physics to help develop techniques to actually see the tiny protein clumps with the human eye, which enables them to be studied.

Yu: “My work is more focused on the methodology. It’s an interesting question, ‘how do we think about quantifying a certain protein, especially when these proteins are interesting and complicated?'".

Yu: “To see and understand proteins, we use a technique called single molecular microscopy. This enables us to look at individual molecules, such as proteins, and gives us a very detailed picture of their size and structure.

“My work is to build on this technique and create a highly sensitive test, called an assay, which can tell us more about the changes to different protein aggregates in Parkinson’s.”

Yu works closely with Dr Evgeniia Lobanova, who also joined Professor Klenerman’s laboratory in 2020. Evgeniia, also with a background in physics, works to identify the proteins of interest.

Evgeniia: “My work is to identify which proteins can tell us the most about Parkinson’s. Yu then develops a high-tech method to see these specific proteins.

“The hope is that we can identify a sensitive test which will hopefully pave the way for early diagnosis of Parkinson’s and related movement conditions.

“Me and Yu work together to achieve our common goals. We are proud that as a team we have been able to develop several unique techniques to characterise different proteins. We help each other to make our research more efficient and impactful, and we value the contribution of each other.”

As well as looking at alpha-synuclein, Evgeniia has identified another protein of interest to study. The protein is a biomarker of inflammation, which means it is seen in the body at higher levels when inflammation is present. Inflammation is often seen in the areas of the brain affected by Parkinson’s.

Evgeniia: “Originally, I looked into a protein which is an indication of inflammation. I measured levels of this protein in post-mortem brain tissue of people with Parkinson’s and saw more of these proteins in people with Parkinson’s than in healthy brains.

“There are lots of different proteins that could provide a clue to what’s going on in the brain. When a person notices a change in their movement and comes to the clinic, there are so many different conditions that could be responsible. Early on, a lot of these conditions look the same, and symptoms overlap. This means that a person can often be misdiagnosed.

“The characteristics of protein aggregates that are linked to neurological conditions could be a very suitable measure [to more accurately diagnose people]. We need to check in larger cohorts of samples, and we are working on that.”

What does this research mean for people with Parkinson’s?

David: “We hope to turn this into a blood test that can be used for early diagnosis of Parkinson’s. Having spoken to people [in the Parkinson’s community], if they knew what was going to happen, they could put measures in place before they are suffering the full symptoms of the condition.

“The main idea is that protein aggregates change as you develop any neurodegenerative disease, and the pattern that they change will be different depending if you are developing Parkinson’s or Alzheimer’s or another similar condition.”

The research team continues to contribute to the growing field of research to develop a test that can diagnose Parkinson’s, and other related conditions, years before symptoms show.