The team at WEHI in Melbourne, Australia, have identified a small molecule that can selectively block cell death.

Published in Science Advances, the findings lay the groundwork for next-generation neuroprotective drugs for degenerative conditions, which currently have no cure or treatments to stop their progression.

At a glance

• Researchers have discovered how to block cell death, an important first step towards slowing neurodegenerative conditions.

• The study from team at WEHI, including researchers from the Parkinson’s Disease Research Centre, has revealed new insight into the mechanisms behind cell death and how it is controlled.

• The discovery was made possible through the advanced screening technologies of the National Drug Discovery Centre.

A new hope in the fight against degenerative conditions

Millions of cells are programmed to die in our bodies every day. But excessive cell death can cause degenerative conditions including Parkinson’s disease and Alzheimer’s disease, with the premature death of brain cells a cause of symptoms in these diseases.

Professor Grant Dewson, co-corresponding author and head of the WEHI Parkinson’s Disease Research Centre, said: “Currently there are no treatments that prevent neurons from dying to slow the progression of Parkinson’s. Any drugs that could be able to do this could be game changing.”

The new study aimed to find new chemicals that block cell death and could be useful to treat degenerative diseases in the future.

To identify novel small molecules, the team worked with researchers in the National Drug Discovery Centre, headquartered at WEHI.

A high-throughput screen of over 100,000 chemical compounds identified one that was effective at stopping cells from dying, by interfering with a well-understood cell death protein.

Co-corresponding author Professor Guillaume Lessene said: “We were thrilled to find a small molecule that targets a killer protein called BAX and stops it working.

“While not the case in most cells, in neurons turning off BAX alone may be sufficient to limit cell death.”

Building on decades of pioneering cell death research

The new research builds on decades of world-leading WEHI discoveries in cell death. A pioneering discovery at WEHI in 1988 of a protein that stopped programmed cell death sparked huge interest in the field, and has since led to a new drug to treat cancer.

While drugs that trigger cell death are transforming treatment of certain cancers, the development of cell death blockers — that could be similarly game-changing for neurodegenerative conditions — has proven challenging.

The new molecule targets a killer protein called BAX which kills cells by damaging mitochondria, the powerhouse of cells.

Lead author and Dewson Lab researcher Kaiming Li said: “For the first time we could keep BAX away from mitochondria and keep cells alive using this molecule.

“This could pave the way for next-generation cell death inhibitors to combat degenerative conditions.”

The study demonstrates the potential to identify drugs that block cell death and may open a new avenue to find much-needed disease-modifying drugs for neurodegenerative conditions such as Parkinson’s and Alzheimer’s.

The WEHI Parkinson’s Disease Research Centre is focusing on its expertise in cell death, ubiquitin signalling, mitochondria and inflammation in the hunt for disease-modifying therapies for Parkinson’s.

By using a multidisciplinary approach to build understanding of the mechanisms behind the disease, the centre hopes to accelerate the discovery of drugs to stop disease progression, transforming the lives of those living with the condition.

The new research was supported by the Bodhi Education Fund and the National Health and Medical Research Council.

Over 70% of patients with ovarian cancer are diagnosed at an advanced stage, often presenting with large volumes of ascites. This ascites fluid not only supports the spread of cancer throughout the abdominal cavity but also significantly impairs the body’s immune defences. Understanding how ascites affects the immune system is important for developing better treatments that use the immune system to fight cancer.

In this recent study, researchers from Trinity College Dublin and University College Dublin explored how ascites disrupts immune cell function, with a particular focus on natural killer (NK) cells and T cells, which are key players in the body’s ability to eliminate tumours.

By analysing the contents of ascites fluid from ovarian cancer patients, the team identified a group of fat molecules called phospholipids as key drivers of this immune dysfunction.

Dr Karen Slattery, Research Fellow in the Trinity Translational Medicine Institute, is the first author of the research article just published in leading international journal Science Immunology. She said: “We found that these lipids interfere with NK cell metabolism and suppress their ability to kill cancer cells. Crucially, we also discovered that blocking the uptake of these phospholipids into NK cells using a specific receptor blocker can restore their anti-tumour activity, which offers a compelling new target for therapeutic intervention.”

“This work adds a critical piece to the puzzle of why ovarian cancer is so aggressive and has such poor outcomes. While the immune system is naturally equipped to detect and destroy cancer cells, this function is switched off in many individuals with ovarian cancer, and we now know that this is in part due to the fat-rich environment created by ascites.”

Prof. Lydia Lynch, formerly based in Trinity and now in Princeton University, is the senior author of the research article. She said: “This study marks a significant advancement in ovarian cancer research, identifying a new mechanism underpinning immune failure and laying the foundation for new therapies that could restore immune function in these patients. By targeting the fat-induced suppression of immune cells, future treatments could empower the body’s own immune defences to fight back and in doing so, improve outcomes for ovarian cancer patients.”