Researchers at the Walter and Eliza Hall Institute (WEHI) have discovered a small molecule compound that can selectively block cell death, potentially opening new therapeutic avenues for neurodegenerative diseases like Parkinson's and Alzheimer's disease. The study, published in Science Advances, identifies WEHI-3773 as a promising candidate for developing next-generation neuroprotective drugs.
Novel Mechanism Targets Cell Death Pathway
The research team, including scientists from the WEHI Parkinson's Disease Research Centre, identified WEHI-3773 through a high-throughput screen of over 100,000 chemical compounds conducted in collaboration with the National Drug Discovery Centre. The compound works by targeting BAX, a killer protein that damages mitochondria and triggers cell death.
"We were thrilled to find a small molecule that targets a killer protein called BAX and stops it working," said co-corresponding author Professor Guillaume Lessene. "While not the case in most cells, in neurons turning off BAX alone may be sufficient to limit cell death."
The study revealed that WEHI-3773 inhibits the interaction between voltage-dependent anion channel 2 (VDAC2) and BAX, preventing BAX recruitment to mitochondria and subsequent cell death. This mechanism represents a novel approach to modulating apoptosis effector proteins.
Differential Effects on Cell Death Proteins
The research uncovered contrasting effects of WEHI-3773 on different cell death proteins. While the compound prevents BAX-mediated cell death by blocking its mitochondrial recruitment, it promotes BAK-mediated cell death by limiting inhibitory interactions with VDAC2. In cells expressing both proteins, the BAK activation effect dominates through a feed-forward mechanism where BAK activates BAX.
Lead author Kaiming Li from the Dewson Lab explained the significance: "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."
Addressing Critical Unmet Medical Need
The discovery addresses a significant gap in treating neurodegenerative diseases, where excessive cell death contributes to disease progression. Professor Grant Dewson, co-corresponding author and head of the WEHI Parkinson's Disease Research Centre, emphasized the clinical potential: "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 research builds on decades of pioneering cell death research at WEHI, including a 1988 discovery of a protein that stopped programmed cell death, which eventually led to new cancer treatments. However, developing cell death blockers for neurodegenerative conditions has proven more challenging than creating cell death triggers for cancer therapy.
Validation Through Target Engagement Studies
To confirm WEHI-3773's mechanism of action, researchers performed drug affinity responsive target stability assays. These experiments demonstrated that WEHI-3773 binding to VDAC2 affected its stability against proteolysis in a dose-dependent manner. Incubation of mitochondria with 400 nM WEHI-3773 inhibited VDAC2 proteolysis, supporting direct engagement of the compound with VDAC2 on the mitochondrial membrane.
Future Therapeutic Development
The findings demonstrate that modulating BAK and BAX interactions with VDAC2 represents a viable strategy for affecting their apoptotic activity, despite these proteins being traditionally challenging therapeutic targets. The research team expressed optimism that these data will inform the design of inhibitors targeting BAX and BAK apoptotic activity as potential treatments for neurodegenerative disorders.
The WEHI Parkinson's Disease Research Centre is leveraging its expertise in cell death, ubiquitin signaling, mitochondria, and inflammation to accelerate discovery of disease-modifying therapies. Through a multidisciplinary approach to understanding disease mechanisms, the center aims to transform treatment options for patients with neurodegenerative conditions.
The research was supported by the Bodhi Education Fund and the National Health and Medical Research Council, highlighting the collaborative effort required to advance potential treatments for conditions affecting millions worldwide.
