PINK1 Parkinson’s Disease Research Team: advancing early Parkinson’s drug discovery

Who Dr Sylvie Calligari from the PINK1 Parkinson’s Disease Research Team

What The PINK1 Parkinson’s Disease Research Team has revealed the first 3D structure of a key protein linked to early onset Parkinson’s disease. By showing how the damage-sensing protein PINK1 attaches to mitochondria, they assist drug discovery – opening new paths to remove faulty cell components and slowing or halting disease progression.

Winner of the 2025 UNSW Eureka Prize for Scientific Research.

It would be so amazing to be able to slow or halt the progression of Parkinson’s Disease. Why is understanding the structure of the PINK1 protein an important step in Parkinson’s disease research?

Indeed! Finding a drug that can stop the progression of Parkinson’s disease is a holy grail of the field. For a long time, PINK1 has been a promising drug target - if we can boost PINK1 activity then we can stop brain cells from dying in Parkinson’s disease patients and therefore halt the symptoms. However, no one had ever seen what human PINK1 looks like, or how it sits on damaged mitochondria. By visualising human PINK1 on the surface of damaged mitochondria we now have a 3D map that we can use to design small molecules (drugs) to improve how it works. Prior to knowing what PINK1 looked like, we were essentially trying to fix a broken machine with the lights out in the garage. By visualising PINK1, is like we have turned the lights on, making it much easier to fix.

How long have you been working on this research for and what led to the breakthrough?

The Komander lab has been working on PINK1 for over a decade, starting in David Komander’s lab while based in Cambridge. When David moved his lab to Melbourne in 2018, he continued the work on PINK1 with PhD student Zhong Yan Gan. At that time, no one had been able to make human PINK1 or see what it looks like, so Zhong worked with insect versions of PINK1 and was able to show how the protein is activated, an important insight.

However, to really understand how PINK1 works, we needed to see what it looks like when it docks to the surface of damaged mitochondria. This is where my involvement came in. I was trained as a mitochondrial biochemist, and I joined the Komander lab in 2019 upon moving back to Australia after having worked in one of the top mitochondrial labs in Germany. Many labs around the world had tried and failed to visualise human PINK1 on mitochondria. However, I wanted to tackle the problem using my mitochondrial skill set. I devised an experimental pipeline to extract the mitochondrial from cells, break the mitochondrial surface into pieces and collect all the pieces that had PINK1 on them. Once I had enough PINK1 pieces, we then froze them and looked at them in different orientations under a very specialised cryo-electron microscope. These images allowed us to construct a 3D model of what human PINK1 looks like on a piece of the mitochondrial surface. Since I was not an expert in the use of the cryo-electron microscope required for this work, this part of the work was performed by cryo-EM specialists Alisa Glukhova and Nicholas Kirk. Their exceptional skill and their enthusiasm to help us out made it possible to see human PINK1 for the first time.

Although it was this combination of unique skill sets that led to the breakthrough, funding was also a crucial factor. The experiments were expensive, and we didn’t have government funding for this project. Therefore, this project was funded by philanthropic donations to WEHI’s Parkinson’s Disease Research Centre, in particular the Hugh Christopher Middendorp Testamentary Trust. These generous donations enabled the breakthrough.

How could this discovery eventually lead to new treatments for people with early-onset Parkinson’s disease?

A subset of people who develop early-onset Parkinson’s disease have mutations in PINK1 that prevent it from working effectively. When PINK1 is broken, it cannot signal that mitochondria in the brain are damaged. Instead, damaged mitochondrial build up inside the brain cells where they release toxins that kill the cells. As brain neurons die, Parkinson’s symptoms develop. Using our 3D map of PINK1, we now have a much clearer idea of what we can do to make broken PINK1 work better, and this will help us search for small molecules that make broken PINK1 more effective. For example, one strategy might be to develop small molecules that make PINK1 stick to the surface of mitochondria better.

Excitingly, we also believe PINK1 activators could also have therapeutic potential even in Parkinson’s disease patients that don’t have broken PINK1 mutations, as boosting even healthy PINK1 may result in enhanced cleanup of damaged mitochondria, which is a hallmark of Parkinson’s disease.

What are the next steps for your team?

We are very excited about the new insights that our PINK1 3D model have revealed about how we might be able to develop PINK1 boosting drugs and have already begun our own PINK1 drug discovery campaign. This is a big new endeavour so our team will need to expand to include chemists and specialists in drug screening. It would be amazing to be able to translate our visualisation of human PINK1 into a therapy that can halt the progression of Parkinson’s disease in patients.

What might readers find surprising about the field of Parkinson’s disease research?

When we think of Parkinson’s disease, often we associate it with the movement symptoms, such as tremors and muscle rigidity. So for me, one of the most surprising aspects of Parkinson’s disease was learning how diverse the disease symptoms are in every patient, many of which extend beyond movement symptoms, but still have very profound effects. For example, patients may experience loss of facial expressions which affects their social interactions, some experience depression, constipation, night terrors. Every patient has a different story. I learned this through working with Parkinson’s disease consumers as part of WEHI’s consumer programme.

The big challenge for researchers is trying to understand what causes Parkinson’s disease at a molecular level when the symptoms are so different. We have to consider there are likely several underlying causes of the disease, and this may require different therapeutic approaches for different patients. The more we learn about the disease, the closer we will get to being able to tailor therapeutic approaches to individual patients.

What does winning a Eureka Prize mean to you?

This means so much! As a PhD student I was inspired by the Eureka Prizes – by the groundbreaking research (recognised across all scientific disciplines), and by how effectively the findings are communicated to the public. However, as much as I love it, a career in science is hard, failed experiments and funding rejections are a natural and common part of the job, so although I dreamed of my own Eureka moment, I’m not sure I expected it to turn into reality! It took a while for the news to sink in, but it is really a huge honour, especially considering the other amazing finalists in our category.

For me, this prize has also come at a particularly critical stage of my career, as I try to build my own independent research program. Not only will this public recognition of our work help to attract funding and interest, but it also gives me the confidence and motivation to push forwards.

I am beyond thrilled and proud to win this prize with the rest of the PINK1 Parkinson’s disease research team.

The Australian Museum Eureka Prizes are the country’s most comprehensive national science awards, honouring excellence across the areas of research & innovation, leadership, science engagement, and school science.